Nk-1 antagonist compositions and methods for use in treating depression

ABSTRACT

The present invention describes the combination of a NK1-antagonist with pramipexole or a pharmaceutically acceptable salt or solvate thereof, useful for treating depressive disorders, including major depressive disorder.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/527,215, filed on Jun. 30, 2017, the disclosureof which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention pertains to the field of the treatment ofdepression.

OBJECT OF THE INVENTION

The present invention includes pharmaceutical combinations comprisingthe (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine or apharmaceutically acceptable salt or solvate thereof and an antagonist ofthe neurokinin receptor subtype-1 (“NK₁-antagonist”), includingfixed-dose combinations, and their use for the treatment of majordepressive disorders.

The present invention also includes methods for treating depressivedisorders by administration of an antagonist of the neurokinin receptorsubtype-1 (herein below referred to as “NK1-antagonist”) in combinationwith a pramipexole daily dose that is from up to 10 times, from up to4.7 times, or from 1.1 times to 10 times the maximum pramipexole dailydose recommended for the relief of the motor symptoms of Parkinson'sdisease. The invention also includes use of a NK1-antagonist for thetreatment of depressive disorders in combination with a pramipexoledaily dose that is from up to 10 times, from up to 4.7 times, or from1.1 times to 10 times higher than the maximum pramipexole daily doserecommended for the relief of the motor symptoms of Parkinson's disease.The invention also includes a pharmaceutical composition comprising, asan active ingredient, a high dose of(S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine orpharmaceutically acceptable salt or solvate thereof, in combination witha NK1-antagonist.

Definitions “CGI”: Clinical Global Impression. “CNS”: Central NervousSystem.

“IR”: Immediate Release of the active ingredient from a composition.“ER”: Extended Release of the active ingredient from a composition.

“GI”: Gastro-Intestinal. “AE(s)”: Adverse Effect(s).

“DSM-5”: Diagnostic and Statistical Manual of Mental Disorders, 5^(th)edition.

“HAMD”: Hamilton Depression Rating Scale. “MADRS”: Montgomery and AsbergDepression Rating Scale. “MDD”: Major Depressive Disorder.

“MAOIs”: Monoamine oxidase inhibitors.

“NIMH”: National Institute of Mental Health. “PD”: Parkinson's Disease.

“Persistent depressive disorder”: also called dysthymia.

“PMDD”: Premenstrual Dysphoric Disorder.

-   -   “NK1-antagonist”: an antagonist of the neurokinine receptor        subtype-1, in the literature also referred to as NK1 receptor        antagonist or NK1 receptor inhibitor.    -   “Effective daily dose of NK1-antagonist”: as used herein, refers        to a daily dose of said NK1-antagonist of from 1 μg to 600 mg.    -   “Pramipexole”: the        (S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine,        as active principle including the free base and its        pharmaceutically acceptable salts and solvates, unless otherwise        specified.    -   “Effective daily dose of pramipexole” or “therapeutically        effective dose of pramipexole”: a daily pramipexole dose        equivalent to at least a pramipexole dihydrochloride monohydrate        approved daily dose for the treatment of PD, this effective        daily dose including low daily doses used during the titration        period.    -   “Effective dose/unit form” or “effective dose per unit form”, in        reference to pramipexole: a pramipexole amount per unit form        equivalent to at least a pramipexole dihydrochloride monohydrate        amount per unit form approved for the treatment of PD, this        amount including low amounts per unit form used during the        titration period.    -   “Salts or solvates thereof” or “salts and solvates thereof”,        with reference to any NK1-antagonist or to pramipexole: this        expression indicates that any salt of said pramipexole or said        NK1-antagonist may be solvated with a solvent, normally water.    -   “SSRIs”: Selective serotonin reuptake inhibitors.    -   “NDRIs”: Norepinephrine-dopamine reuptake inhibitors.    -   “TCAs”: Tricyclic antidepressants.    -   “TTS”: Transdermal Therapeutic System.    -   “Depressive disorders”: include, but are not limited to, major        depressive disorder (MDD), persistent depressive disorder        (dysthymia), Bipolar depression, seasonal affective disorder        (SAD), psychotic depression, premenstrual dysphoric disorder        (PDD), peripartum (postpartum) depression, situational        depression, and atypical depression. The common feature of these        depressive disorders is the presence of sad, empty, or irritable        mood, accompanied by somatic and cognitive changes that        significantly affect the individual's capacity to function. The        difference among these disorders are issues of duration, timing        or presumed etiology. See Depressive Disorders, Diagnostic and        Statistical Manual of Mental Disorders, Fifth Edition,        dsm.psychiatryonline.org/doi/10.1176/appi.books.9780890425596.dsm04.    -   “Maximum tolerated dose,” “maximal tolerated dose” or “MTD”        refers to, and is defined as the highest dose of a drug or        treatment that does not cause unacceptable side effects. For        instance, the maximum tolerated dose is determined in clinical        trials by testing increasing doses on different groups of people        until the highest dose with acceptable side effects is found.        The dose of the pramipexole may be higher than the maximum        tolerated dose of pramipexole for the treatment of depression        when administered alone. In particular, from 1.1 to 10 times        higher than the maximal tolerated dose of pramipexole for the        treatment of depression when administered alone, which includes,        but is not limited to a dose from 1.5 to 10 times higher than        the maximal tolerated dose of pramipexole for the treatment of        depression when administered alone, a dose from 2.5 to 10 times        higher than the maximal tolerated dose of pramipexole for the        treatment of depression when administered alone, a dose from 3        to 10 times higher than the maximal tolerated dose of        pramipexole for the treatment of depression when administered        alone, a dose from 4 to 10 times higher than the maximal        tolerated dose of pramipexole for the treatment of depression        when administered alone, and a dose from 6 to 10 times higher        than the maximal tolerated dose of pramipexole for the treatment        of depression when administered alone.

BACKGROUND OF THE INVENTION

Major depressive disorder (MDD), also referred to as depression orclinical depression, is a common but serious mood disorder associatedwith a significant burden, affecting around 16% of the population in theUS in their lifetime (reviewed in de Souza et al, 2015). Depression isone of the most common mental disorders in the U.S. Current researchsuggests that depression is caused by a combination of genetic,biological, environmental, and psychological factors.

The estimated costs of MDD are around 83 billion US Dollars annually,due to many psychosocial factors including loss of workdays (reviewed inde Souza et al, 2015). Estimates are that on average a depressed personloses 27.2 workdays per year (reviewed in de Souza et al, 2015). Asignificant part of the burden corresponds to unsuccessful treatments.Remission of depressive symptoms is achieved in only one-third of theMDD patients after the first antidepressant trial (reviewed in de Souzaet al, 2015), and unsuccessful treatments contribute substantially tothe observed suffering and social costs of MDD.

Signs and symptoms of depression typically include the following:persistent sad, anxious, or “empty” mood; feelings of hopelessness, orpessimism; irritability; feelings of guilt, worthlessness, orhelplessness; loss of interest or pleasure in hobbies and activities;decreased energy or fatigue; moving or talking more slowly; feelingrestless or having trouble sitting still; difficulty concentrating,remembering, or making decisions; difficulty sleeping, early-morningawakening, or oversleeping; appetite and/or weight changes; thoughts ofdeath or suicide, or suicide attempts; aches or pains, headaches,cramps, or digestive problems without a clear physical cause and/or thatdo not ease even with treatment (NIMH, Health and Education, MentalHealth Information as posted on the NIMH Web Site). Not everyone who isdepressed experiences every symptom. Some people experience only a fewsymptoms while others may experience many. For a diagnosis ofdepression, signs and symptoms have to be present most of the day,nearly every day, for at least two weeks (DSM-5)

Depression can happen at any age (NIMH, Health and Education, MentalHealth Information as posted on the NIMH Web Site), but often begins inadulthood. Depression is now recognized as occurring in children andadolescents, although it sometimes presents with more prominentirritability than low mood. Depression, especially in midlife or olderadults, can co-occur with other serious medical illnesses, such asdiabetes, cancer, heart disease, and Parkinson's disease. Risk factorsinclude: personal or family history of depression; major life changes,trauma, or stress; certain physical illnesses and medications.

Some forms of depression are slightly different, or develop under uniquecircumstances (NIMH, Health and Education, Mental Health Information asposted on the NIMH Web Site), such as:

Persistent depressive disorder (also called dysthymia) with early orlate onset and with or without atypical features, is a depressed moodthat lasts for at least two years. A person diagnosed with persistentdepressive disorder may have episodes of major depression along withperiods of less severe symptoms, but symptoms must last for two years tobe considered persistent depressive disorder.Perinatal depression is much more serious than the “baby blues”(relatively mild depressive and anxiety symptoms that typically clearwithin two weeks after delivery) that many women experience after givingbirth. Women with perinatal depression experience full-blown majordepression during pregnancy or after delivery (postpartum depression).The feelings of extreme sadness, anxiety, and exhaustion that accompanyperinatal depression may make it difficult for these new mothers tocomplete daily care activities for themselves and/or for their babies.Psychotic depression occurs when a person has severe depression plussome form of psychosis, such as having disturbing false fixed beliefs(delusions) or hearing or seeing upsetting things that others cannothear or see (hallucinations). The psychotic symptoms typically have adepressive “theme,” such as delusions of guilt, poverty, or illness.Seasonal affective disorder is characterized by the onset of depressionduring the winter months, when there is less natural sunlight. Thisdepression generally lifts during spring and summer. Winter depression,typically accompanied by social withdrawal, increased sleep, and weightgain, predictably returns every year in seasonal affective disorder.Mood dysregulation disorder (diagnosed in children and adolescents;DSM-5).

Premenstrual Dysphoric Disorder (PMDD; DSM-5).

Bipolar Disorder is different from depression, but it is included inthis list because patients with bipolar disorder experience episodes ofextremely low moods that meet the criteria for major depression (called“bipolar depression”). Bipolar disorder is a persistent, episodic anddebilitating condition with an estimated lifetime prevalence of over2.0%, including both types I (with mania) and II (with hypomania)(reviewed in Poon et al, 2015). Bipolar disorder is associated withrecurring episodes of mania, hypomania, mixed manicdepressive states, orpsychosis, as well as prominent major depression and dysthymia, as wellas prevalent anxiety symptoms—all leading to high risks of potentiallysevere functional impairment, substance abuse, and high rates ofsuicide, accidents, and increased mortality from co-occurring medicalillnesses—all despite use of available pharmacological and psychosocialtreatments (Poon et al, 2015). The depressive components of the disorderhave been especially difficult to treat successfully and they accountfor three-quarters of the several weeks of follow-up with treatment thatinclude clinically significant residual morbidity (reviewed in Poon etal, 2015).

Other mood disorders encompassed within the term “depression” includeAlzheimer's disease with depressed mood, depressed mood in Parkinson'sdisease, Lewy body disease, and other dementias, post-stroke depression,schizoaffective disorders, adjustment disorder with depressed mood, anddrug- and alcohol-induced depressed mood.

Depression is usually initially treated with medications andpsychotherapy. If the treatments do not reduce symptoms,electroconvulsive therapy and other brain stimulation therapies mayhelp. Medications include the following (Mayo Clinic):

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine(Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), citalopram(Celexa) and escitalopram (Lexapro).Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine(Cymbalta), venlafaxine (Effexor XR), desvenlafaxine (Pristiq, Khedezla)and levomilnacipran (Fetzima).Norepinephrine-dopamine reuptake inhibitors (NDRIs). Bupropion(Wellbutrin, Aplenzin, Forfivo XL) falls into this category.Atypical antidepressants such as trazodone and mirtazapine (Remeron),vortioxetine (Brintellix) and vilazodone (Viibryd).Tricyclic antidepressants (TCAs) such as imipramine (Tofranil),nortriptyline (Pamelor), amitriptyline, doxepin, trimipramine(Surmontil), desipramine (Norpramin) and protriptyline (Vivactil)—can bevery effective, but tend to cause more-severe side effects than newerantidepressants. Tricyclics are therefore usually considered as secondline therapy.Monoamine oxidase inhibitors (MAOIs), such as tranylcypromine (Parnate),phenelzine (Nardil) and isocarboxazid (Marplan), may be prescribed,typically when other medications haven't worked. However, MAOIs areusually not first line antidepressant therapy, because they can haveserious interactions with certain foods and some medications includingbirth control pills, decongestants and certain herbal supplements.Selegiline TTS (Emsam), a newer MAOI, may cause fewer side effects thanother MAOIs.

One disadvantage of all of the above antidepressant medications is thatthey typically take 2 to 4 weeks to start having an antidepressanteffect.

(S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine(pramipexole) is a synthetic aminothiazole derivative, described in U.S.Pat. No. 4,886,812, the content of which is incorporated herein byreference. It is a dopamine autoreceptor agonist (Schneider and Mierau1987) that is approved for the treatment of the symptoms of Parkinson'sdisease (PD), in doses ranging from 0.375 mg/day to 4.5 mg/day, given in3 equally divided doses (Mirapex® Prescribing Information May 2018) orin a single dose once a day (Mirapex ER® Prescribing Information, July2016). Pramipexole is supplied in tablets for immediate releasecontaining 0.125 mg, 0.25 mg, 0.5 mg, 1 mg and 1.5 mg of pramipexoledihydrochloride monohydrate; and in tablets for extended releasecontaining 0.375 mg, 0.75 mg, 1.5 mg, 3 mg and 4.5 mg of pramipexoledihydrochloride monohydrate. It is structurally distinct from theergot-derived drugs (e.g., bromocriptine and pergolide). Pramipexole isa dopamine D2 receptor agonist that is also pharmacologically unique inthat it is a full agonist and has receptor selectivity for the dopamineD3 receptor subtype of the D2 subfamily of receptors. These propertiesmay confer advantages in terms of both efficacy (full agonist withpotential for greater therapeutic effects) and safety (receptorselectivity may reduce unwanted side effects) compared to currentlyavailable dopamine agonists (Piercey, 1998).

Literature reports that pramipexole was also found to be effective inthe treatment of depressive symptoms in patients with PD, albeit with asmall effect size. A 12-week, double-blind, placebo controlled trial in296 PD patients was conducted with pramipexole (0.125 to 1.0 mg giventhree times per day). The primary endpoint was the Beck DepressionInventory scale (BDI). Results showed that BDI scores decreased by anadjusted 5.9 (SE 0.5) in the pramipexole group, and 4.0 (SE 0.5) in theplacebo group. The difference between the 2 treatment groups wassignificant (p=0.01; Barone et al, 2010), although the magnitude of theeffect size was small. In addition, other small, often open-labelstudies in which pramipexole was added on to antidepressant treatment(augmentation) also showed modest but significant efficacy in favor ofpramipexole in non-PD patients with major depressive disorder (MDD;Cusin et al, 2013; Goldberg et al, 2004), including non-PD patients withtreatment resistant depression (Hori and Kunigi, 2012; Pae, et al, 2013;Fawcett et al, 2016), or patients with depression associated withbipolar disorder (reviewed in Sienaert et al, 2013; Dell'Osso andKetter, 2013; Tondo et al, 2014). However, Kleebatt et al (2017) intheir review judged that clear proof of antidepressant efficacy had notbeen obtained for pramipexole, and attributed this to low levels ofevidence, small sample sizes or discordant results. In all thesereports, the dose of pramipexole remained within the range approved forthe treatment of the motor symptoms of PD, even when the title of thepublication mentions “high doses” of pramipexole (Fawcett et al, 2016).Since in most of these studies, efficacy appeared to be modest, higherdoses of pramipexole were tested in a randomized, prospective,double-blind, placebo-controlled, fixed-dose study (Corrigan et al,2000). A total of 174 eligible patients with a DSM-III-R diagnosis ofmajor depression (single or recurrent episode, with or withoutmelancholia and without psychotic features) were assigned to one of fivetreatment groups: placebo group, fluoxetine group (20 mg/day), or one ofthree pramipexole groups (0.375 mg/day; 1 mg/day; 5 mg/day). Patientsreceived a 1-week placebo run-in, 8 weeks of treatment, and a 1-weekpost-study follow-up assessment (week 9). Efficacy was measuredprimarily by the change from baseline in the HAM-D (17-item version)total score, MADRS total score, and the CGI-Severity of Illness (SI)score. Results showed that the majority of patients in each treatmentgroup completed the study (66-86%), with the exception of thepramipexole 5.0 mg group (42.4%). In the pramipexole 5.0 mg group, 57.6%of patients discontinued treatment prematurely, mainly because ofadverse events (AEs), 76% of patients reported nausea, and 39% reportedvomiting. At endpoint (week 8), the pramipexole 1.0 mg group and thefluoxetine group showed significantly better improvement over baselinethan the placebo group on the HAMD (p=0.0076) and on the MADRS. Thepramipexole 5.0 mg group had the best improvement at week 8 (−15.00),but p values were not available for this test against placebo because ofthe high drop-out rate.

Taken together, the results reported by Corrigan et al (2000) suggestthat higher doses of pramipexole could be more effective, but doseshigher than the approved doses cannot be used because of a highincidence of dose-limiting adverse events (AEs), notably nausea andvomiting but also non-G.I. adverse effects such as diaphoresis, lightheadedness and headache. Also, animal studies support the suggestionthat high doses of pramipexole should be more effective for thetreatment of depression. For example, high doses of pramipexole provedto be active in diverse tests of animal behavior simulating symptoms ofdepression, including Willner's Anhedonia Test (Willner et al., 1994),Fixed Interval Test, Forced Swimming Test, and REM Sleep InhibitionTest.

Due to the pramipexole AEs, however, the problem of providing safe,chronic, effective treatment of a patient suffering from depression withpramipexole has remained unsolved.

SUMMARY OF THE INVENTION

The present invention relates to increasing the therapeutic window forpramipexole, for the treatment of depressive disorders, including MDD,to safely enable its full antidepressant efficacy. In particular, thepresent invention relates to a combination of a NK1-antagonist withpramipexole, to increase the therapeutic window of said pramipexole.

It has been found that a NK1-antagonist, by reducing or even abrogatingthe side effects of high doses of pramipexole, enables the fullantidepressant potential of pramipexole.

Thus, the safe administration of pramipexole doses that are higher, andeven much higher, than the maximum daily dose recommended for the reliefof the symptoms of Parkinson's disease (such as motor symptoms),provides significant improvement to patients suffering from depressivedisorders.

Alternatively, the safe administration of pramipexole doses that arehigher, and even much higher than the maximum tolerated dose for therelief of symptoms of Parkinson's disease (such as motor symptoms),provides significant improvement to patients suffering from depressivedisorders.

More particularly, it has been found that, in the case of pramipexoledihydrochloride monohydrate, its combination with said NK1-antagonistallows the administration of a therapeutic effective dose of saidpramipexole dihydrochloride monohydrate that will significantly exceedthe maximum recommended dose (4.5 mg/day) of pramipexole dihydrochloridemonohydrate for the treatment of the symptoms of PD, thus increasing itsefficacy in the treatment of a patient suffering from a depressivedisorder, including MDD.

More particularly, it has been found that the combination of pramipexoleor a pharmaceutically acceptable salt or solvate thereof with aNK1-antagonist allows the administration of a therapeutic effective dosethat may be equivalent to from up to 10 times, from up to 4.7 times, orfrom 1.1 times to 10 times higher than the aforementioned maximum doseof pramipexole dihydrochloride monohydrate recommended for the treatmentof the symptoms of PD.

The combination of a NK1-antagonist with pramipexole or apharmaceutically acceptable salt or solvate thereof acts by enabling thefull antidepressant efficacy of pramipexole, due to the high pramipexoledoses that may be used in combination with said NK1-antagonist.

It has also been found that, in patients suffering from a depressivedisorder, daily doses of pramipexole (in pramipexole dihydrochloridemonohydrate) ranging from more than 4.5 mg to 45 mg/day, up to from 15mg to 45 mg/day, in combination with a NK1-antagonist normally indicatedfor the prevention of postoperative nausea and vomiting or of thechemotherapy-induced nausea and vomiting, offer significant efficacy anda fast onset of action.

More particularly, it been found that, in the treatment of patientssuffering from a depressive disorder, the use of a NK1-antagonist incombination with daily doses of pramipexole or pharmaceuticallyacceptable salt or solvate thereof that are equivalent to from more than4.5 mg to 21 mg/day and even from more than 6 mg to 21 mg or from 15 mgto 21 mg of pramipexole dihydrochloride monohydrate, also offersignificant efficacy and a fast onset of action.

It has also been found that, by using said NK1 receptor antagonist, alsoreferred to as NK1 receptor inhibitor or simply NK1-antagonist, incombination with pramipexole or a pharmaceutically acceptable salt orsolvate thereof, it is possible to treat a patient suffering fromdepression by maintaining an effective pramipexole or pharmaceuticallyacceptable salt or solvate thereof daily dose with minimal adverseeffect.

Thus, the present invention provides a pharmaceutical combinationcomprising

-   (a) a NK1-antagonist; and-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof.

In particular, the present invention provides a pharmaceuticalcombination comprising

-   (a) a NK1-antagonist; and-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof, at a daily dose (in pramipexole dihydrochloride    monohydrate) that is higher than the maximum dose of pramipexole    dihydrochloride monohydrate recommended for the relief of the motor    symptoms of PD,    for use for the treatment of depressive disorders, including MDD.

Said pramipexole daily dose in said combination is from up to 10 times,from up to 4.7 times, or from 1.1 times to 10 times higher than themaximum dose of pramipexole dihydrochloride monohydrate recommended forthe relief of the motor symptoms of PD.

The present invention further provides the use of a NK1-antagonist forenabling the full antidepressant efficacy of pramipexole in thetreatment of MDD.

Moreover, the invention provides a method for treating a patientsuffering from a depressive disorder, which comprises treating saidpatient with a NK1-antagonist, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof.

Moreover, the invention provides a method for treating a patientsuffering from a depressive disorder, which comprises treating saidpatient with a NK1-antagonist, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof at a daily dose (inpramipexole dihydrochloride monohydrate) from up to 10 times, from up to4.7 times, or from 1.1 times to 10 times higher than the maximum dailydose recommended for the relief of the symptoms of Parkinson's diseasesuch as motor symptoms (4.5 mg/day).

The daily dose of the NK1-antagonist is from 1 μg to 600 mg and thepramipexole daily dose (in pramipexole dihydrochloride monohydrate),depending on the degree of gravity of the illness and the age andcondition of the patient and including low doses for use during thetitration period, will range from 0.375 mg to 45 mg, normally from 0.375mg to 21 mg. For treating depression, said daily dose preferably is frommore than 4.5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg to45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg, normally from morethan 4.5 mg to 21 mg, in particular from more than 6 mg to 21 mg, from10 mg to 21 mg, from 13 mg to 21 mg or from 15 mg to 21 mg.

According to an embodiment, for said use or said method, saidNK1-antagonist, in an amount per unit form of from 1 μg to 600 mg orfrom 1 mg to 600 mg, and said pramipexole or pharmaceutically acceptablesalt or solvate thereof, in an amount equivalent to from 0.125 mg to 45mg, from more than 4.5 mg to 21 mg or from more than 6 mg to 21 mg, areeach formulated in a pharmaceutical composition in admixture with apharmaceutical carrier or vehicle and separately administered,concurrently or sequentially, to a patient in need of treatment withsaid combination, and in particular to a patient suffering from adepressive disorder, including MDD.

According to another embodiment, said NK1-antagonist and saidpramipexole or pharmaceutically acceptable salt or solvate thereof aremixed together and formulated in a pharmaceutical composition(fixed-dose combination), in admixture with a pharmaceutical carrier, tobe administered to a patient in need of said treatment.

According to this embodiment, said NK1-antagonist, in an amount of from1 μg to 600 mg or from 1 mg to 600 mg, and said pramipexole orpharmaceutically acceptable salt or solvate thereof, in an amountequivalent to from 0.125 mg to 45 mg, preferably from more than 4.5 mgto 45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg, from 13 mgto 45 mg, from 15 mg to 45 mg, from more than 4.5 mg to 21 mg or frommore than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg, from15 mg to 21 mg of pramipexole dihydrochloride monohydrate, are mixedtogether and formulated in a pharmaceutical composition (fixed-dosecombination), in admixture with a pharmaceutical carrier or vehicle, tobe administered to a patient in need of said treatment.

According to the invention, said NK1-antagonist may also be formulatedin a pharmaceutical composition comprising said NK1-antagonist in anamount per unit form of from 1 μg to 600 mg or from 1 mg to 600 mg, inadmixture with a pharmaceutical carrier or vehicle, for use forpreventing or curing the adverse effects of pramipexole daily doses thatfor some patients may be higher, and even much higher, than the maximumdose (4.5 mg/day) presently recommended for the relief of the motorsymptoms of Parkinson's disease.

For its use for the treatment of a depressive disorder, including MDD,in combination with a NK1-antagonist, pramipexole is formulated in apharmaceutical composition in dosage unit form comprising saidpramipexole in an amount per IR- or ER-form (including low doses to beused during the titration period) equivalent to from 0.125 mg to 45 mg,advantageously from more than 4.5 mg to 45 mg, from more than 6 mg to 45mg, from 10 mg to 45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg ofpramipexole dihydrochloride monohydrate.

In particular, for said use in combination with a NK1-antagonist,pramipexole is formulated in a pharmaceutical composition in dosage unitform comprising said pramipexole an amount per IR-form (including lowdoses to be used during the titration period) equivalent to from 0.125mg to 22.5 mg, advantageously from 1.5 mg to 22.5 mg, from more than 3mg to 22.5 mg, from 5 mg to 22.5 mg, from 6.5 mg to 22.5 mg, or from 7.5mg to 22.5 mg of pramipexole dihydrochloride monohydrate.

For said use in combination with a NK1-antagonist, pramipexole, isformulated in a pharmaceutical composition in dosage unit formcomprising said pramipexole an amount per ER-form (including low dosesto be used during the titration period) equivalent to from 0.375 mg to45 mg, from more than 4.5 mg to 45 mg, from 5 mg to 45 mg, from morethan 6 mg to 45 mg, from 10 mg to 45 mg from 13 mg to 45 mg, or from 15mg to 45 mg of pramipexole dihydrochloride monohydrate.

According to an embodiment, the dose of pramipexole or pharmaceuticallyacceptable salt or solvate thereof, in pramipexole dihydrochloridemonohydrate, per IR- or ER-unit form, will range from 0.125 mg to 21 mg,advantageously from 1.6 mg 21 mg, from 1.8 mg to 21 mg, from 2.4 mg to21 mg, from 3 mg to 21 mg, more advantageously from more than 4.5 mg to21 mg, preferably from more than 6 mg to 21 mg, from 10 mg to 21 mg,from 13 mg to 21 mg, or from 15 mg to 21 mg.

Preferably, according to this embodiment, the dose per unit form ofpramipexole or pharmaceutically acceptable salt or solvate thereof in anER formulation, including slow-release compositions and transdermaltherapeutic systems such as transdermal patches, for the treatment of adepressive disorder, including MDD, will range from an amount that isequivalent to from more than 4.5 mg to 21 mg, in particular from 4.8 mgto 21 mg or from more than 6 mg to 21 mg of pramipexole dihydrochloridemonohydrate, depending on the tolerability (in combination with saidNK1-antagonist).

In the aforementioned combinations with pramipexole, at the abovedoses/unit form,

-   -   if the NK1-antagonist is aprepitant, the dose/unit form will        range from 10 mg to 250 mg;    -   if the NK1-antagonist is rolapitant, the dose/unit form will        range from 30 mg to 270 mg.

DETAILED DESCRIPTION

The present invention concerns a NK1-antagonist Component (a), as anadverse events inhibitor, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof Component (b) at adaily dose equivalent to from up to 10 times, up to 4.7 times, or from1.1 times to 10 times higher than the maximal pramipexoledihydrochloride monohydrate dose approved for the treatment of motorsymptom of Parkinson's disease. Said combination, including fixed-dosecombinations, is useful for the treatment of depressive disorders,including MDD. Said combination, including fixed-dose combinations, isalso for use for the treatment of depressive disorders, including MDD.

The present invention also concerns a NK1-antagonist Component (a), asan adverse events inhibitor, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof Component (b) at adaily dose equivalent to from 1.1 to 10 times higher than the maximaltolerated dose of pramipexole for the treatment of depression whenadministered alone. Such a daily dose includes, but is not limited to adose from 1.1 to 10 times higher than the maximal tolerated dose ofpramipexole for the treatment of depression when administered alone, adose from 1.5 to 10 times higher than the maximal tolerated dose ofpramipexole for the treatment of depression when administered alone, adose from 2.5 to 10 times higher than the maximal tolerated dose ofpramipexole for the treatment of depression when administered alone, adose from 3 to 10 times higher than the maximal tolerated dose ofpramipexole for the treatment of depression when administered alone, adose from 4 to 10 times higher than the maximal tolerated dose ofpramipexole for the treatment of depression when administered alone, anda dose from 6 to 10 times higher than the maximal tolerated dose ofpramipexole for the treatment of depression when administered alone.

In particular, the invention concerns, according to its aspects,

-   -   a method for treating depressive disorders, including MDD by        administration of a NK1-antagonist to a patient in combination        with an effective pramipexole or pharmaceutically acceptable        salt thereof daily dose;    -   a NK1-antagonist Component (a), for use for the treatment of        depressive disorders, including MDD, in a patient, in        combination with, as Component (b), a pramipexole or        pharmaceutically acceptable salt or solvate thereof daily dose;    -   the use of a NK1-antagonist for the preparation of a medicament        for the treatment of depressive disorders, including MDD, in a        patient, in combination (including fixed-dose combination) with        an effective daily dose of pramipexole or a pharmaceutically        acceptable salt thereof;    -   the use of a NK1-antagonist for the preparation of a medicament        for the treatment of a depressive disorder, including MDD, said        medicament consisting of a pharmaceutical composition in dosage        unit form comprising, as an active ingredient, said        NK1-antagonist and, as another active ingredient, pramipexole or        a pharmaceutically acceptable salt thereof; and    -   a method (or use) of a NK1-antagonist as an inhibitor of the        adverse effects of pramipexole in the treatment of a depressive        disorder, including MDD.

The present invention also relates to a fixed-dose combination (a/b)comprising said NK1-antagonist Component (a) and said pramipexole orpharmaceutically acceptable salt or solvate thereof Component (b) in apharmaceutical composition in dosage unit form in admixture with apharmaceutically acceptable carrier or vehicle. This fixed-dosecombination is useful and is for use for the treatment of depressivedisorders, including MDD, in a patient.

The NK1-Antagonist Component (a)

Any of the NK1-antagonists disclosed in the literature is an usefuladverse effect inhibitor of pramipexole and may be safely used, asComponent (a), in combination with a dose of pramipexole orpharmaceutically acceptable salt or solvate thereof Component (b) thatis equivalent to from up to 10 times, from up to 4.7 times, or from 1.1times to 10 times higher than the maximum pramipexole dihydrochloridemonohydrate daily dose recommended for the relief of the motor symptomsof PD.

Any of the NK1-antagonists disclosed in the literature is an usefuladverse effect inhibitor of pramipexole and may be safely used, asComponent (a), in combination with a dose of pramipexole orpharmaceutically acceptable salt or solvate thereof Component (b) thatis equivalent to from 1.1 to 10 times higher than the maximal tolerateddose of pramipexole for the treatment of depression when administeredalone. Such a dose includes, but is not limited to a dose from 1.1 to 10times higher than the maximal tolerated dose of pramipexole for thetreatment of depression when administered alone, a dose from 1.5 to 10times higher than the maximal tolerated dose of pramipexole for thetreatment of depression when administered alone, a dose from 2.5 to 10times higher than the maximal tolerated dose of pramipexole for thetreatment of depression when administered alone, a dose from 3 to 10times higher than the maximal tolerated dose of pramipexole for thetreatment of depression when administered alone, a dose from 4 to 10times higher than the maximal tolerated dose of pramipexole for thetreatment of depression when administered alone, and a dose from 6 to 10times higher than the maximal tolerated dose of pramipexole for thetreatment of depression when administered alone.

Advantageously, said NK1-antagonist Component (a) is selected from thegroup consisting of

-   -   5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (aprepitant); described in U.S. Pat. No. 5,719,147, and in a        liquid oral formulation, in US 2017/0035774, and in an        injectable emulsion in a single-dose vial for intravenous use        containing 130 mg aprepitant in 18 ml of emulsion (Cinvanti®),        described in U.S. Pat. No. 9,808,465 (the contents of each        disclosure is incorporated herein in its entirety by reference);    -   [3-{[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]        ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl}-5-oxo-2H-1,2,4-triazol-1-yl]phosphonic        acid (fosaprepitant), disclosed, for example as meglumine salt        in U.S. Pat. No. 5,691,336 and as di(cyclohexylamine) salt in US        2016/355533, the disclosures of which are incorporated herein in        their entirety by reference;    -   (2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide        (casopitant) described in U.S. Pat. No. 7,294,630, the        disclosure of which incorporated herein in its entirety by        reference;    -   (2S)-1-[(3aS,4S,7aS)-4-hydroxy-4-(2-methoxyphenyl)-7,7-diphenyl-1,3,3a,5,6,7a-hexahydroisoindol-2-yl]-2-(2-methoxyphenyl)propan-1-one        (INN: dapitant);    -   (2S,3S)—N-(5-tert-Butyl-2-methoxybenzyl)-2-(diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-amine        (maropitant), disclosed in U.S. Pat. No. 5,807,867,        WO2005/082416 and EP 3173071 the contents of each of which are        incorporated herein in its entirety by reference;    -   (2S,3S)-2-Diphenylmethyl-3-[(5-isopropyl-2-methoxybenzyl)amino]quinuclidine        (eziopitant), disclosed by Evangelista S (2001). “Eziopitant.        Pfizer”; Current Opinion in Investigational Drugs: 2 (10):        1441-3; reviewed in Drugs: the Investigational Drugs Journal 6        (8): 758-72;    -   (2S)—N-{2-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-[4-(cyclopropylmethyl)piperazin-1-yl]-N-methyl-2-phenylacetamide        (INN figopitant);    -   N-[(2R)-1-[Acetyl-[(2-methoxyphenyl)methyl]amino]-3-(1H-indol-3-yl)propan-2-yl]-2-(4-piperidin-1-ylpiperidin-1-yl)acetamide        (lanepitant);    -   2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide        (netupitant) described in U.S. Pat. Nos. 6,297,375, 6,719,996        and 6,593,472, and, in an oral composition, comprising 300 mg of        netupitant and palonosetron hydrochloride in an amount        equivalent to 0.5 mg of palonosetron base, herein below referred        to as “netupitant-300/palonosetron-0.5”, l described in U.S.        Pat. No. 8,951,969, the disclosures of which are incorporated        herein in their entirety by reference;    -   {4-[5-{2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamido}-4-(2-methylphenyl)pyridin-2-yl]-1-methylpiperazin-1-ium-1-yl}methyl        hydrogen phosphate (INN: fosnetupitant), described in WO        2013/082102 and, in a pure crystalline form, in US 2017/0096442,        available in an injectable composition, comprising 235 mg of        fosnetupitant and palonosetron hydrochloride in an amount        equivalent to 0.25 mg of palonosetron base (Akynzeo® for        injection), herein below referred to as        “netupitant-235palonosetron-0.25”, the disclosures of which are        incorporated herein in their entirety by reference;    -   (2R,4S)-4-[(8aS)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide        maleate (orvepitant), described in U.S. Pat. Nos. 7,652,012 and        8,309,553, the disclosures of which are incorporated herein in        their entirety by reference;    -   (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one        (rolapitant), described in U.S. Pat. No. 7,049,320 and, for an        injectable form thereof, in U.S. Pat. No. 9,101,615, the        disclosures of which are incorporated herein in their entirety        by reference;    -   3-((3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy]-4-(4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-ylcyclopent-2-en-1-one        (serlopitant) described in U.S. Pat. Nos. 7,544,815 and        7,217,731, the disclosures of which are incorporated herein in        their entirety by reference;    -   2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l-carboxylic acid        [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide        (vestipitant), described in WO 2001/25219 and, in intravenous        formulation having a reduced tendency to cause hemolysis, in WO        2012/175434, the disclosure of which is incorporated herein in        their entirety by reference; and    -   (2S,3S)—N-[(2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenylmethyl]-2-phenylpiperidin-3-amine        (GR2015171, vofopitant), described in U.S. Pat. No. 5,703,240        (see also U.S. Pat. No. 8,093,268) and also disclosed by Gardner        C J et al. Regul Pept. 1996 Aug. 27; 65(1):45-53, the        disclosures of which are incorporated herein in their entirety        by reference;        and pharmaceutically acceptable salts of each of said        NK1-antagonists.

Illustrative examples of pharmaceutically acceptable salts of basicadvantageous NK1-antagonists include acid addition salts with mineralacids, such as hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, phosphoric acid, nitric acid, carbonic acid, phosphoricacid and the like and acid addition salts with organic acids such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, ascorbic acid, methanesulfonic acid,ethanesulfonic acid, gluconic acid, aspartic acid, glutamic acid. andthe like.

Illustrative examples of pharmaceutically acceptable salts of acidicNK1-antagonists such as fosaprepitant include salts with inorganic basessuch as alkaline metal or alkaline-earth metal salts, and salts withorganic bases such as dicyclohexylamine salts, N-methyl-D-glucamine(meglumine) salts, and salts with amino acids, as described in U.S. Pat.No. 5,691,336, the contents of which is incorporated herein in itsentirety by reference.

An advantageous NK1-antagonists to be used in combination with6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is selectedfrom the group consisting of

-   -   aprepitant and pharmaceutically acceptable salts and solvates        thereof,    -   fosaprepitant and pharmaceutically acceptable salts and solvates        thereof,    -   casopitant and pharmaceutically acceptable salts and solvates        thereof,    -   maropitant and pharmaceutically acceptable salts and solvates        thereof,    -   eziopitant and pharmaceutically acceptable salts and solvates        thereof,    -   lanepitant and pharmaceutically acceptable salts and solvates        thereof,    -   netupitant and pharmaceutically acceptable salts and solvates        thereof,    -   orvapitant and pharmaceutically acceptable salts and solvates        thereof,    -   rolapitant and pharmaceutically acceptable salts and solvates        thereof,    -   serlopitant and pharmaceutically acceptable salts and solvates        thereof,    -   vestipitant and pharmaceutically acceptable salts and solvates        thereof,    -   vofopitant and pharmaceutically acceptable salts and solvates        thereof, and    -   netupitant-300/palonosetron-0.5.

Aprepitant, fosaprepitant meglumine, fosaprepitant di(cyclohexylamine),rolapitant, rolapitant hydrochloride and netupitant-300/palonosetron-0.5are particularly advantageous NK1-antagonists.

Antagonists of the NK1 receptor that are approved for the prevention ortreatment of postoperative nausea and vomiting or for the prevention ofchemotherapy-induced nausea and vomiting are particularly usefulaccording to the present invention. In particular, aprepitant iscommercially available (Emend®) in capsules containing 40 mg, 80 mg, or125 mg aprepitant or, as fosaprepitant dimeglumine (Emend® Injection),in vials containing 115 mg or 150 mg fosaprepitant; rolapitant isavailable (Varubi®) in 90-mg tablets; and netupitant is available(Akynzeo®) in a fixed-dose combination in capsules containing 300 mg ofnetupitant and 0.5 mg of the 5HT3-antagonist palonosetron (ashydrochloride), herein below referred to as “netupitant 300mg/palonosetron 0.5 mg”. Each of these preparations is a particularlyadvantageous NK1-antagonist Component (a) for the combination withpramipexole or pharmaceutically acceptable salts and solvates thereofComponent (b) according to the present invention.

In the aforementioned method, use and combination, including fixed-dosecombinations, said NK1-antagonist is present in an amount per unit formand is administered at a daily dose of 1 μg to 600 mg, normally from 1mg to 600 mg, or from 1 mg to 300 mg.

More particularly, in said combination, said NK1-antagonist is selectedfrom the group consisting of aprepitant and pharmaceutically acceptablesalts and solvates thereof, at a daily dose equivalent to from 10 mg to250 mg of aprepitant; fosaprepitant and pharmaceutically acceptablesalts and solvates thereof, at a daily dose equivalent to from 10 mg to250 mg of aprepitant; rolapitant and pharmaceutically acceptable saltsand solvates thereof, at a daily dose equivalent to from 15 mg to 270 mgof rolapitant; netupitant and pharmaceutically acceptable salts andsolvates thereof, at a daily dose equivalent to from 300 mg to 600 mg ofnetupitant; and netupitant-300/palonosetron-0.5.

Preferably, for said use in the treatment of depressive disorders,including MDD, in a patient, said NK1-antagonist Component (a) isaprepitant at a daily oral dose of from 10 mg to 250 mg; rolapitant, ata daily oral dose of from 30 mg to 270 mg or netupitant 300mg/palonosetron 0.5 mg, orally administered once a day, each incombination with pramipexole or a pharmaceutically acceptable saltthereof Component (b) at a daily dose equivalent to from up to 10 times,from up to 4.7 times, or from 1.1 times to 10 times higher than themaximum recommended dose for the treatment of the motor symptoms ofParkinson's disease.

Preferably, for said use in the treatment of depressive disorders,including MDD, in a patient, said NK1-antagonist Component (a) isaprepitant at a daily oral dose of from 10 mg to 250 mg; rolapitant, ata daily oral dose of from 30 mg to 270 mg or netupitant 300mg/palonosetron 0.5 mg, orally administered once a day, each incombination with pramipexole or a pharmaceutically acceptable saltthereof Component (b) at a daily dose equivalent to from 1.1 to 10 timeshigher than the maximal tolerated dose of pramipexole for the treatmentof depression when administered alone. Such a daily dose includes, butis not limited to a dose from 1.1 to 10 times higher than the maximaltolerated dose of pramipexole for the treatment of depression whenadministered alone, a dose from 1.5 to 10 times higher than the maximaltolerated dose of pramipexole for the treatment of depression whenadministered alone, a dose from 2.5 to 10 times higher than the maximaltolerated dose of pramipexole for the treatment of depression whenadministered alone, a dose from 3 to 10 times higher than the maximaltolerated dose of pramipexole for the treatment of depression whenadministered alone, a dose from 4 to 10 times higher than the maximaltolerated dose of pramipexole for the treatment of depression whenadministered alone, and a dose from 6 to 10 times higher than themaximal tolerated dose of pramipexole for the treatment of depressionwhen administered alone.

For its administration to a patient suffering from a depressivedisorder, including MDD, in combination with pramipexole, each of theabove NK1-antagonists is formulated in a pharmaceutical composition indosage unit form comprising, as an active ingredient, saidNK1-antagonist, in admixture with a pharmaceutical carrier or vehicle.

In particular, said NK1-antagonist active ingredient of saidpharmaceutical composition is selected from the group consisting ofaprepitant and pharmaceutically acceptable salts and solvates thereof,in an amount, per unit form, equivalent to from 10 mg to 250 mg ofaprepitant; fosaprepitant and pharmaceutically acceptable salts andsolvates thereof, in an amount, per unit form, equivalent to from 10 mgto 250 mg of aprepitant; rolapitant and pharmaceutically acceptablesalts and solvates thereof, in an amount, per unit form, equivalent tofrom 15 mg to 270 mg of rolapitant; netupitant and pharmaceuticallyacceptable salts and solvates thereof, in an amount, per unit form,equivalent to from 300 mg to 600 mg of netupitant; andnetupitant-300/palonosetron-0.5.

Advantageously, said NK1-antagonist is aprepitant, in an amount per unitform of from 10 mg to 250 mg; fosaprepitant meglumine, in an amount perunit form equivalent to from 10 mg to 250 mg of aprepitant; orrolapitant, in an amount per unit form of from 15 mg to 270 mg or from30 mg to 270 mg.

As set forth above, by using a NK1-antagonist in combination withpramipexole or a pharmaceutically acceptable salt or solvate thereof, itis possible to treat a patient suffering from a MDD by maintaining aneffective pramipexole or pharmaceutically acceptable salt or solvatethereof daily dose with minimal adverse effect.

Thus, in order to assure a sure, safe and concurrent administration ofsaid NK1-antagonist and said pramipexole, the present invention providesa fixed-dose combination consisting of a pharmaceutical composition indosage unit form comprising an effective amount per unit form of saidNK1-antagonist and an effective amount per unit form of pramipexole, inadmixture with a pharmaceutical carrier or vehicle.

These NK1-antagonist/pramipexole fixed-dose combinations are describedin “The fourth aspect of the invention” section below.

The Pramipexole Component (b)

A stated in the Definitions, the term “pramipexole” generally stands for(S)-6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, as freebase (pramipexole) or as pharmaceutically acceptable salts and solvatesthereof, including pramipexole dihydrochloride monohydrate, their dosesper unit form and their daily doses being expressed as equivalents ofpramipexole dihydrochloride monohydrate.

Pharmaceutically acceptable salts or solvates of pramipexole are alsoincluded in the present invention.

Illustrative examples of pharmaceutically acceptable salts of saidpramipexole include acid addition salts with mineral acids such ashydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,nitric acid, phosphoric acid and the like or with organic acids such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, carbonic acid, methanesulfonic acid,ethanesulfonic acid, aspartic acid, glutamic acid and the like. Thesolvation agent is generally water.

Among pramipexole and pharmaceutically acceptable salts or solvatesthereof, pramipexole dihydrochloride monohydrate, commerciallyavailable, is preferred, but pramipexole base may be preferably used forsome circumstance, for example in transdermal therapeutic systems.Stable pharmaceutical compositions comprising pramipexoledihydrochloride monohydrate, disclosed in WO 2012/0140604 and in WO2008/122638, the contents of each of which are incorporated herein byreference in their entirety; and sustained release compositionscomprising pramipexole dihydrochloride monohydrate, disclosed in U.S.Pat. No. 8,399,016, the contents of which is incorporated herein byreference in its entirety, may be useful for use in combination with aNK1-antagonist for the treatment of a depressive disorder, includingMDD.

As set forth in the definitions, the effective daily dose of pramipexoleis a dose equivalent to at least the pramipexole dihydrochloridemonohydrate approved daily dose for the treatment of PD. Said dailyapproved dose is from 0.375 mg to 4.5 mg. However, it is herebyspecified that, according to the present invention, the combination of aNK1-antagonist with said pramipexole allows the administration ofpramipexole dihydrochloride monohydrate at daily doses as high as thoseapproved for the treatment of Parkinson's disease without any adverseeffect, but also allows the administration of pramipexoledihydrochloride monohydrate daily doses that are higher and also muchhigher than said approved doses. For example, the dose of pramipexole ora pharmaceutically acceptable salt thereof may be a daily doseequivalent to from up to 10 times, from up to 4.7 times, or from 1.1times to 10 times higher than the maximum recommended dose for thetreatment of the symptoms of Parkinson's disease (such as motorsymptoms).

The effective daily dose of pramipexole may also be a dose equivalent toat least a maximal tolerated dose of pramipexole dihydrochloridemonohydrate used for the treatment symptoms of PD (such as motorsymptoms). For example, the effective daily dose of pramipexole or apharmaceutically acceptable salt thereof may be a daily dose equivalentto from 1.1 to 10 times higher than a dose equivalent to at least amaximal tolerated dose of pramipexole dihydrochloride monohydrate usedfor the treatment of depression when administered alone. Such aneffective daily dose, includes but is not limited to, a dose equivalentto a dose from 1.1 to 10 times higher than the maximal tolerated dose ofpramipexole dihydrochloride monohydrate used for the treatment ofdepression when administered alone, a dose from 1.5 to 10 times higherthan the maximal tolerated dose of pramipexole dihydrochloridemonohydrate used for the treatment of depression when administeredalone, a dose equivalent to a dose from 2.5 to 10 times higher than themaximal tolerated dose of pramipexole dihydrochloride monohydrate usedfor the treatment of depression when administered alone, a doseequivalent to a dose from 3 to 10 times higher than the maximaltolerated dose of pramipexole dihydrochloride monohydrate used for thetreatment of depression when administered alone, a dose equivalent to adose from 4 to 10 times higher than the maximal tolerated dose ofpramipexole dihydrochloride monohydrate used for the treatment ofdepression when administered alone, and a dose equivalent to a dose from6 to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate used for the treatment of depression whenadministered alone.

For the treatment of depressive disorders, including MDD, in combinationwith a NK1-antagonist as described in “The NK1-antagonist Component (a)”section above, pramipexole is formulated in a pharmaceutical compositioncomprising said pramipexole in an amount equivalent to from 0.125 mg to45 mg of pramipexole dihydrochloride monohydrate in admixture with apharmaceutical carrier or vehicle. Said composition is administered to apatient in need of said treatment at daily dose of from 0.375 mg to 45mg in combination with a NK1-antagonist at a daily dose of 1 μg to 600mg, normally from 1 mg to 600 mg.

In particular, in said combination with a NK1-antagonist, pramipexoledihydrochloride monohydrate may be administered to a patient, includingpediatric patients, suffering from a depressive disorder, including MDD,at a daily dose equivalent to from 0.375 mg to 45 mg, from more than 4.5mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg, from 10mg to 45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg, normally from0.375 mg to 21 mg, from more than 4.5 mg to 21 mg, from more than 6 mgto 21 mg, from 10 mg to 21 mg, from 13 mg to 21 mg, or from 15 mg to 21mg of pramipexole dihydrochloride monohydrate; depending on thetolerability (in combination with the NK1-antagonist).

For its administration to a patient suffering from a depressivedisorder, including MDD, in combination with an NK1-antagonist asdescribed above in “The NK1-Antagonist Component (a)” section, the6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine is formulatedin a pharmaceutical composition in dosage unit form comprising, as anactive ingredient, said6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, in admixturewith a pharmaceutical carrier or vehicle.

According to the present invention, pramipexole or a pharmaceuticallyacceptable salt or solvate thereof, is in a pharmaceutical compositionin dosage unit form comprising said pramipexole or a pharmaceuticallyacceptable salt or solvate thereof in an amount per unit form equivalentto from 0.125 mg to 45 mg of pramipexole dihydrochloride monohydrate.

For its use for the treatment of a depressive disorder, including MDD,in combination with a NK1-antagonist, pramipexole is formulated in apharmaceutical composition in dosage unit form comprising saidpramipexole in an amount per IR- or ER-form (including low doses to beused during the titration period) equivalent to from 0.125 mg to 45 mg,advantageously from more than 4.5 mg to 45 mg, from more than 6 mg to 45mg, from 10 mg to 45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg ofpramipexole dihydrochloride monohydrate.

In particular, said pharmaceutical composition Component (b) comprises,as an active ingredient, pramipexole or a pharmaceutically acceptablesalt thereof in an amount per unit form equivalent to from 0.125 mg to22.5 mg, normally from 1.5 mg to 22.5 mg, from more than 3 mg to 22.5mg, from 5 mg to 22.5 mg, from 6.5 mg to 22.5 mg, or from 7.5 mg to 22.5mg of pramipexole dihydrochloride monohydrate, in an IR-formulation, orin an amount per unit form equivalent to from 0.375 mg to 45 mg, frommore than 4.5 mg to 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45mg, from 10 mg to 45 mg from 13 mg to 45 mg, or from 15 mg to 45 mg ofpramipexole dihydrochloride monohydrate in an ER-formulation. Saidamounts per unit form include low amounts for use of said unit formsduring the titration period.

In a preferred embodiment, in order to provide the treatment of adepressive disorder, including MDD, with high pramipexole doses, theinvention provides a pharmaceutical composition in dosage unit formcomprising, as an active ingredient, pramipexole or a pharmaceuticallyacceptable salts or solvates thereof in an amount per unit formequivalent to from 15 mg to 45 mg, from 15 mg to 30 mg, or from 15 mg to21 mg of pramipexole dihydrochloride monohydrate, in admixture with apharmaceutical carrier or vehicle.

As set forth above, a NK1-antagonist, in combination with pramipexole ora pharmaceutically acceptable salt or solvate thereof, can be used totreat a patient suffering from a depressive disorder, including MDD, bymaintaining a therapeutically effective pramipexole or pharmaceuticallyacceptable salt or solvate thereof daily dose with minimal adverseeffect.

In order to provide concurrent administration of said NK1-antagonist andof said pramipexole or pharmaceutically acceptable salt or solvatethereof, the invention also provides a fixed-dose combination comprisinga pharmaceutical composition in dosage unit form comprising, as activeingredients, a NK1-antagonist; and pramipexole or pharmaceuticallyacceptable salts and solvates thereof, in admixture with apharmaceutical carrier or vehicle.

The NK1-antagonist pramipexole fixed-dose combinations will be describedin “The Pharmaceutical Compositions” section below.

First Aspect of the Invention

According to a first aspect, the present invention includes a method forsafely treating a depressive disorder, including MDD, in patientssuffering from a depressive disorder, with pramipexole by concurrentlyadministering to said patients a NK1-antagonist.

More particularly, the invention provides a method for treating apatient suffering from a depressive disorder, including MDD, whichcomprises administering to a patient in need of said treatment aneffective dose of said NK1-antagonist in combination with an effectivedaily dose of pramipexole or a pharmaceutically acceptable salt thereof.

According to a preferred embodiment,

said NK1-antagonist is selected from the group consisting of aprepitantand pharmaceutically acceptable salts and solvates thereof,fosaprepitant and pharmaceutically acceptable salts and solvatesthereof, rolapitant and pharmaceutically acceptable salts and solvatesthereof, netupitant and pharmaceutically acceptable salts and solvatesthereof, and netupitant-300/palonosetron-0.5; each at a daily dosedescribed in “The NK1-antagonist Component (a)” section, except fornetupitant-300/palonosetron-0.5 which is provided once a day or every2-4 days; and

said pramipexole or pharmaceutically acceptable salts or solvatesthereof is administered at a daily dose as described above in “Thepramipexole Component (b)” section.

According to an advantageous embodiment, in the method of the presentinvention the NK1-antagonist is aprepitant, fosaprepitant meglumine, orrolapitant and the pramipexole or a pharmaceutically acceptable salt orsolvate thereof is pramipexole dihydrochloride monohydrate, each at thedaily doses described in the respective sections.

In carrying out the method of the present invention, the daily dose ofthese NK1-antagonists is at least as high as that for preventing ortreating nausea and vomiting in patients undergoing a surgical operationor cancer chemotherapy according to the current protocols for saidtreatment or prevention. Said daily dose is from 1 μg to 600 mg,normally from 1 mg to 600 mg, or from 1 mg to 300 mg.

The pramipexole or a pharmaceutically acceptable salt or solvate thereofdaily dose is equivalent to from 0.375 mg to 45 mg of pramipexoledihydrochloride monohydrate, including daily doses used during thetitration period.

A NK1-antagonist selected from the group consisting of aprepitant andpharmaceutically acceptable salts and solvates thereof and rolapitantand pharmaceutically acceptable salt and solvate thereof is aparticularly advantageous NK1-antagonist.

Preferably, in said combination, said NK1-antagonist is aprepitant andsaid pramipexole or a pharmaceutically acceptable salt or solvatethereof is pramipexole dihydrochloride monohydrate.

In particular, said NK1-antagonist in said combination is aprepitant, atan effective daily dose of from 10 mg to 250 mg and said pramipexole orpharmaceutically acceptable salt or solvate thereof in said combinationis pramipexole dihydrochloride monohydrate, at an effective daily dosein a range selected from the group consisting of from more than 4.5 mgto 45 mg, from 5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mgto 45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg.

In carrying out the method (or use) of the present invention, saidNK1-antagonist and said pramipexole or pharmaceutically acceptable saltor solvate thereof are each formulated in a pharmaceutical compositionin dosage unit form comprising, respectively, said NK1-antagonist andsaid pramipexole or pharmaceutically acceptable salt or solvate thereof,each in admixture with a pharmaceutical carrier or vehicle.

Said NK1-antagonist and said pramipexole or pharmaceutically acceptablesalt or solvate thereof may also be in a fixed-dose combination,co-formulated in a pharmaceutical composition in dosage unit formcomprising an effective amount per unit form of said NK1-antagonist, andan effective amount per unit form of said pramipexole orpharmaceutically acceptable salts and solvates thereof, in admixturewith a pharmaceutical carrier or vehicle. This fixed dose combinationwill be described herein below in the fourth aspect of the invention.

The doses per unit form of said NK1-antagonist and of said pramipexoleare described above, respectively, in “The NK1-antagonist Component (a)”and in “The pramipexole Component (b)” sections.

In particular, in said composition, said NK1-antagonist is present in anamount per unit form of from 1 μg to 600 mg or from 1 mg to 600 mg.

In said composition said pramipexole or pharmaceutically acceptable saltor solvate thereof is present in an amount per unit form equivalent tofrom 0.125 mg to 45 mg or from 0.125 mg to 21 mg of pramipexoledihydrochloride monohydrate.

In particular, said NK1-antagonist active ingredient of saidpharmaceutical composition is selected from the group consisting ofaprepitant and pharmaceutically acceptable salts and solvates thereof,in an amount, per unit form, equivalent to from 10 mg to 250 mg ofaprepitant; fosaprepitant and pharmaceutically acceptable salts andsolvates thereof, in an amount, per unit form, equivalent to from 10 mgto 250 mg of aprepitant; rolapitant and pharmaceutically acceptablesalts and solvates thereof, in an amount, per unit form, equivalent tofrom 15 mg to 270 mg of rolapitant; netupitant and pharmaceuticallyacceptable salts and solvates thereof, in an amount, per unit form,equivalent to from 300 mg to 600 mg; andnetupitant-300/palonosetron-0.5. Advantageously, said NK1-antagonist isaprepitant, in an amount per unit form of from 10 mg to 250 mg;fosaprepitant meglumine, in an amount per unit form equivalent to from10 mg to 250 mg of aprepitant; or rolapitant, in an amount per unit formof from 15 mg to 270 mg or from 30 mg to 270 mg.

Said pramipexole dose per unit form consists of or includes an amountper unit form equivalent to a range selected from the group consistingof from 0.125 mg to 45 mg, from more than 4.5 mg to 45 mg, from 5 mg to45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg, from 13 mg to45 mg, and from 15 mg to 45 mg of pramipexole dihydrochloridemonohydrate.

According to an embodiment, in the method of the present invention theNK1-antagonist is aprepitant or rolapitant, and pramipexole or apharmaceutically acceptable salt or solvate thereof is administered at adaily dose that is equivalent to from up to 10 times, from up to 4.7times, or from 1.1 times to 10 times higher than the maximum recommendedpramipexole dihydrochloride monohydrate dose approved for the relief ofthe symptoms of PD (such as motor symptoms).

According to another embodiment, in the method of the present inventionthe NK1-antagonist is aprepitant or rolapitant, and pramipexole or apharmaceutically acceptable salt or solvate thereof is administered at adaily dose that is equivalent to a dose from 1.1 times to 10 timeshigher than a maximal tolerated dose of pramipexole dihydrochloridemonohydrate dose for the treatment of depression when administeredalone. Such a daily dose, includes but is not limited to, a daily dosethat is equivalent to a dose from 1.1 to 10 times higher than themaximal tolerated dose of pramipexole dihydrochloride monohydrate dosefor the treatment of depression when administered alone, a dose from 1.5to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 2.5to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 3 to10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 4 to10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, and a daily dose that is equivalent to a dose from 6to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone.

According to this embodiment, in said method (or use), saidNK1-antagonist, at the aforementioned effective daily dose, isadministered to said patient, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof administered to saidpatient at a daily dose equivalent to from more than 4.5 mg to 21 mg,normally from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mgto 21 mg or from 15 mg to 21 mg of pramipexole dihydrochloridemonohydrate.

Preferably, according to this embodiment, in the method for treating adepressive disorder, including MDD, in an adult patient according to thepresent invention, said NK1-antagonist is aprepitant, at a daily oraldose of from 10 mg to 250 mg; or rolapitant, at a daily oral dose offrom 30 mg to 270 mg, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof, at an effectivedaily oral dose corresponding to from more than 4.5 mg to 21 mg,normally from more than 6 mg to 21 mg, from 10 mg to 21 mg, from 13 mgto 21 mg, or from 15 mg to 21 mg of .pramipexole dihydrochloridemonohydrate.

Second Aspect of the Invention

According to a second aspect, the invention provides a NK1-antagonistfor use in combination with pramipexole or a pharmaceutically acceptablesalt or solvate thereof for the treatment of a depressive disorder,including MDD, in a patient in need of said treatment.

In particular, this second aspect of the present invention provides

-   (a) a NK1-antagonist, in combination with-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof, at a dose level (in pramipexole dihydrochloride    monohydrate) that is from up to 10 times, from up to 4.7 times, or    from 1.1 times to 10 times higher than the maximum pramipexole    dihydrochloride monohydrate daily dose recommended for the relief of    the symptoms of Parkinson's disease (such as motor symptoms),    for use for the treatment of depressive disorder, including MDD, in    a patient.

Any of the NK1-antagonists described in “The NK1-antagonist Component(a)” section may be used, normally in a dosage unit form, according tothis second aspect of the invention.

In particular, this second aspect of the present invention provides aNK1-antagonist, in an amount per unit form of from 1 μg to 600 mg,normally from 1 mg to 600 mg or from 1 mg to 300 mg, for use incombination with a daily dose of said pramipexole or pharmaceuticallyacceptable salt or solvate thereof (including low doses used in thetitration period) equivalent to from 0.375 mg to 45 mg of pramipexoledihydrochloride monohydrate, for the treatment of a depressive disorder,including MDD, in a patient in need of said treatment.

For the use according to this second aspect of present invention, thedaily dose of said NK1-antagonist is at least as high as that forpreventing or treating nausea and vomiting in patients undergoing asurgical operation or cancer chemotherapy according to the currentprotocols for said treatment or prevention. Said daily dose will rangefrom 1 μg to 600 mg, normally from 1 mg to 600 mg or from 1 mg to 300mg.

For its use for the treatment of a depressive disorder, including MDD,according to the present invention, the NK1-antagonist, at theaforementioned effective daily dose, as described in “The NK1-antagonistComponent (a)” section, is administered to a patient in need of saidtreatment in combination with pramipexole at the aforementionedeffective daily dose, as described in “The pramipexole Component (b)”section.

Normally, for its use according to this second aspect, the inventionprovides said NK1-antagonist Component (a), in a pharmaceuticalcomposition comprising, as an active ingredient, said NK1-antagonist, inadmixture with a pharmaceutical carrier or vehicle, for use for thetreatment of a depressive disorder, including MDD, in a patient, incombination with pramipexole or a pharmaceutically acceptable salt orsolvate thereof Component (b), also in a pharmaceutical composition, inadmixture with a pharmaceutical carrier or vehicle, to be administeredto said patient at a daily dose that is equivalent to from up to 10times, from up to 4.7 times, or from 1.1 times to 10 times higher thanthe maximum pramipexole dihydrochloride monohydrate daily doserecommended for the relief of the motor symptoms of Parkinson's disease(such a motor symptoms).

As another use according to this second aspect, the invention providesNK1-antagonist Component (a), in a pharmaceutical compositioncomprising, as an active ingredient, said NK-1 antagonist, in admixturewith a pharmaceutical carrier or vehicle, for the use of the treatmentof a depressive disorder, including MDD, in a patient, in combinationwith pramipexole or a pharmaceutically acceptable salt or solvatethereof Component (b), also in a pharmaceutical composition, inadmixture with a pharmaceutical carrier or vehicle, to be administeredto said patient at a daily dose that is equivalent to a dose from 1.1times to 10 times higher than a maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone. Such a daily dose, includes but is not limited to, adaily dose that is equivalent to a dose from 1.1 to 10 times higher thanthe maximal tolerated dose of pramipexole dihydrochloride monohydratedose for the treatment of depression when administered alone, a dailydose that is equivalent to a dose from 1.5 to 10 times higher than themaximal tolerated dose of pramipexole dihydrochloride monohydrate dosefor the treatment of depression when administered alone, a daily dosethat is equivalent to a dose from 2.5 to 10 times higher than themaximal tolerated dose of pramipexole dihydrochloride monohydrate dosefor the treatment of depression when administered alone, a daily dosethat is equivalent to a dose from 3 to 10 times higher than the maximaltolerated dose of pramipexole dihydrochloride monohydrate dose for thetreatment of depression when administered alone, a daily dose that isequivalent to a dose from 4 to 10 times higher than the maximaltolerated dose of pramipexole dihydrochloride monohydrate dose for thetreatment of depression when administered alone, and a daily dose thatis equivalent to a dose from 6 to 10 times higher than the maximaltolerated dose of pramipexole dihydrochloride monohydrate dose for thetreatment of depression when administered alone.

Said pharmaceutical composition in dosage unit form comprises saidNK1-antagonist Component (a), in an amount of from 1 μg to 600 mg, inadmixture with a pharmaceutical carrier or vehicle, and is for use forthe treatment of a depressive disorder, including MDD, in a patient, incombination with pramipexole or a pharmaceutically acceptable salt orsolvate thereof Component (b), in doses, in pramipexole dihydrochloridemonohydrate, from up to 10 times, from up to 4.7 times, or from 1.1times to 10 times higher than the daily dose approved for the relief ofthe symptoms of PD (such as motor symptoms).

Said pharmaceutical composition in dosage unit form comprises saidNK1-antagonist Component (a), in an amount of from 1 μg to 600 mg, inadmixture with a pharmaceutical carrier or vehicle, and is for use forthe treatment of a depressive disorder, including MDD, in a patient, incombination with pramipexole or a pharmaceutically acceptable salt orsolvate thereof Component (b), in doses, in pramipexole dihydrochloridemonohydrate, from 1.1 times to 10 times higher than a maximal tolerateddose of pramipexole dihydrochloride monohydrate dose for the treatmentof depression when administered alone. Such a dose, includes but is notlimited to, a daily dose that is equivalent to a dose from 1.1 to 10times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 1.5to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 2.5to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 3 to10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 4 to10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, and a daily dose that is equivalent to a dose from 6to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone.

According to an embodiment, said NK1-antagonist, in an amount per unitform of from 1 μg to 600 mg, is for use in the treatment of a depressivedisorder, including MDD, in a patient in combination with a pramipexole,also in a pharmaceutical composition in dosage unit form comprising saidpramipexole in an amount per unit form equivalent to from 0.125 mg to 45mg, from more than 4.5 mg to 45 mg, from more than 6 mg to 45 mg, from10 mg to 45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg ofpramipexole dihydrochloride monohydrate, to be administered to saidpatient at a daily dose equivalent to from 0.375 mg to 45 mg, from morethan 4.5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg,from 13 mg to 45 mg, or from 15 mg to 45 mg of pramipexoledihydrochloride monohydrate.

In particular, said NK1-antagonist is selected from the group consistingof aprepitant and pharmaceutically acceptable salts and solvatesthereof, in an amount per unit form equivalent to from 10 mg to 250 ofaprepitant; fosaprepitant and pharmaceutically acceptable salts andsolvates thereof, in an amount per unit form equivalent to from 10 mg to250 of aprepitant; rolapitant and pharmaceutically acceptable salts andsolvates thereof, in an amount per unit form equivalent to from 15 mg to270 mg of rolapitant; netupitant and pharmaceutically acceptable saltsand solvates thereof, in an amount per unit form equivalent to from 300mg to 600 mg; and netupitant-300/palonosetron-0.5.

Advantageously, said NK1-antagonist is aprepitant, in an amount per unitform of from 10 mg to 250 mg; fosaprepitant meglumine, in an amount perunit form equivalent to from 10 mg to 250 mg of aprepitant; orrolapitant, in an amount per unit form of from 15 mg to 270 mg or from30 mg to 270 mg.

Pramipexole, in said combination, may be formulated in a pharmaceuticalcomposition in IR- or ER-form, in an amount per unit form as describedin “The pramipexole Component (b)” section and administered twice tothree times per day in an IR-formulation or once a day in anER-formulation, at the aforementioned daily doses, in combination withthe NK1-antagonist.

Third Aspect of the Invention

According to this third aspect, the present invention provides the useof a NK1-antagonist for the preparation of a medicament for thetreatment of a depressive disorder, including MDD, in a patient in needof said treatment, in combination with pramipexole or a pharmaceuticallyacceptable salt or solvate thereof.

This third aspect of the invention provides the use of saidNK1-antagonist Component (a), for the preparation of a medicamentconsisting of a pharmaceutical composition comprising, as an activeingredient, said NK1-antagonist, in an amount of from 1 μg to 600 mg, inadmixture with a pharmaceutical carrier or vehicle, for the treatment ofa depressive disorder, including MDD, in a patient, in combination withpramipexole or a pharmaceutically acceptable salt or solvate thereofComponent (b), at a daily dose, (in pramipexole dihydrochloridemonohydrate) from up to 10 times, from up to 4.7 times, or from 1.1times to 10 times higher than the daily dose approved for the relief ofthe symptoms of PD (such as motor symptoms).

This third aspect of the invention also provides the use of saidNK1-antagonist Component (a), for the preparation of a medicamentconsisting of a pharmaceutical composition comprising, as an activeingredient, said NK1-antagonist, in an amount of from 1 μg to 600 mg, inadmixture with a pharmaceutical carrier or vehicle, for the treatment ofa depressive disorder, including MDD, in a patient, in combination withpramipexole or a pharmaceutically acceptable salt or solvate thereofComponent (b), at a daily dose, (in pramipexole dihydrochloridemonohydrate) from 1.1 times to 10 times higher than a maximal tolerateddose of pramipexole dihydrochloride monohydrate dose for the treatmentof depression when administered alone. Such a daily dose, includes butis not limited to, a daily dose that is equivalent to a daily dose thatis equivalent to a dose from 1.1 to 10 times higher than the maximaltolerated dose of pramipexole dihydrochloride monohydrate dose for thetreatment of depression when administered alone, a dose from 1.5 to 10times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 2.5to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 3 to10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, a daily dose that is equivalent to a dose from 4 to10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone, and a daily dose that is equivalent to a dose from 6to 10 times higher than the maximal tolerated dose of pramipexoledihydrochloride monohydrate dose for the treatment of depression whenadministered alone.

For this use, said NK1-antagonist is formulated in a medicamentconsisting of or comprising a pharmaceutical composition in dosage unitform to be administered to a patient suffering from a depressivedisorder, including MDD, in combination with pramipexole or apharmaceutically acceptable salt or solvate thereof, also in apharmaceutical composition in dosage unit form.

The above medicament consisting of or comprising combinations ofpharmaceutical compositions, for use for the treatment of depressivedisorder, including MMD, in a patient, normally are in dosage unit form,in an IR or ER formulation, and each of said compositions may comprise

-   (a) said NK1-antagonist, in admixture with a pharmaceutical carrier    or vehicle, and/or-   (b) said pramipexole or pharmaceutically acceptable salt or solvate    thereof, in admixture with a pharmaceutical carrier or vehicle, or-   (a/b) both said NK1-antagonist and said pramipexole or    pharmaceutically acceptable salt or solvate thereof, in a fixed-dose    combination comprising said NK1-antagonist and said pramipexole or    pharmaceutically acceptable salt or solvate thereof in admixture    with a pharmaceutical carrier or vehicle.

These medicament consisting of or comprising combinations ofpharmaceutical compositions, each pharmaceutical composition comprisingComponent (a) and/or Component (b) or the (a/b)-fixed-dose combination,are useful and for use for the treatment of depressive disorder,including MMD, in a patient.

Thus, this third aspect of the invention provides the use of aNK1-antagonist for the preparation of a pharmaceutical composition indosage unit form comprising, as an active ingredient in admixture with apharmaceutical carrier or vehicle, said NK1-antagonist in an amount perunit form of form 1 μg to 600 mg (for use) for the treatment of adepressive disorder, including MDD, in a patient in need of saidtreatment, in combination with pramipexole, also in a pharmaceuticalcomposition in dosage unit form comprising, in admixture with apharmaceutical carrier or vehicle, said pramipexole in an amount perunit form equivalent to from 0.125 mg to 45 mg of pramipexoledihydrochloride monohydrate, to be administered to said patient at adaily dose equivalent to from 0.375 mg to 45 mg of pramipexoledihydrochloride monohydrate.

As set forth above, the above pramipexole dose-range (daily and per unitform) includes low doses to be used during the titration period.

In particular, in said pharmaceutical combination,

-   (a) said NK1-antagonist is present in said composition in an amount    per unit form of from 1 μg to 600 mg, to be administered at a daily    dose of from 1 mg to 600 mg; and-   (b) said pramipexole Component (b) is present in said composition in    an amount per unit form equivalent to from 0.125 mg to 45 mg, from    more than 4.5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg    to 45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg, to be    administered at a daily dose equivalent to from 0.375 mg to 45 mg,    preferably from more than 4.5 mg to 45 mg, from more than 6 mg to 45    mg, from 10 mg to 45 mg, from 13 mg to 45 mg, or from 15 mg to 45 mg    of pramipexole dihydrochloride monohydrate.

According to an embodiment of this third aspect, the invention providesa medicament consisting of or comprising a pharmaceutical combinationcomprising, as Components,

-   Component (a) a NK1-antagonist, in a pharmaceutical composition in    dosage unit form comprising, as an active ingredient, said    NK1-antagonist, in an amount per unit form of from 1 mg to 600 mg,    in admixture with a pharmaceutical carrier or vehicle; and-   Component (b) pramipexole or a pharmaceutically acceptable salt or    solvate thereof, in a pharmaceutical composition in dosage unit form    comprising, as an active ingredient, said pramipexole or a    pharmaceutically acceptable salt or solvate thereof, in an amount    per unit form equivalent to from 0.125 mg to 21 mg of pramipexole    dihydrochloride monohydrate, in admixture with a pharmaceutical    carrier or vehicle.

The pharmaceutical combination according to this third aspect of theinvention may be administered to patients suffering from a depressivedisorder, including MDD, with the intent of finding and adopting a safeand effective pramipexole daily dose with higher therapeutic efficacythan is used or known in the art, for the heretofore unachievedtreatment or alleviation of symptoms of said depressive disorder,including MDD, in each patient. Normally, Component (a) and Component(b) are concurrently or sequentially administered to said patientsuffering from a depressive disorder, including MDD.

Any of the aforementioned NK1-antagonists may be used as an activeingredient of the pharmaceutical composition Component (a) of thecombination according to this third aspect of the invention. Preferably,said NK1-antagonist is selected from the group consisting of aprepitant,in an amount per unit form of from 10 mg to 250 mg; fosaprepitantdimeglumine, in an amount per unit form of from 10 mg to 150 mg,rolapitant, in an amount per unit form of from 30 mg to 270 mg andnetupitant, in an amount per unit form of from 100 mg to 600 mg. If saidNK1-antagonist is netupitant, in an amount per unit form of from 100 mgto 600 mg, the above pharmaceutical composition Component (a) may alsocomprise, as a second active ingredient, palonosetron or apharmaceutically acceptable salt thereof, in an amount per unit formequivalent to from 0.1 mg to 0.5 mg of palonosetron base.

In the pharmaceutical composition Component (b), pramipexole orpharmaceutically acceptable salt or solvate thereof, is in an amount perunit form equivalent to from 0.125 mg to 45 mg, in particular from morethan 4.5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg,from 13 mg to 45 mg, or from 15 mg to 45 mg of pramipexoledihydrochloride monohydrate.

In particular, the dose of pramipexole or pharmaceutically acceptablesalt or solvate thereof per IR-unit form, for the treatment of adepressive disorder, including MDD, will range from an amount equivalentto from 0.125 mg to 22.5 mg, from 1.5 to 22.5 mg, from more than 3 mg to22.5 mg, from 5 mg to 22.5 mg, from 6.5 mg to 22.5 mg, or from 10 mg to22.5 mg of pramipexole dihydrochloride monohydrate, depending on safetyand tolerability (in combination with the NK1-antagonist).

The dose per unit form of pramipexole or pharmaceutically acceptablesalt or solvate thereof in an ER formulation, including slow-releasecompositions and transdermal therapeutic systems such as transdermalpatches, for the treatment of a depressive disorder, including MDD, willrange from an amount that is equivalent to from 0.375 mg to 45 mg, from5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg from 13mg to 45 mg, or from 15 mg to 45 mg of pramipexole dihydrochloridemonohydrate, depending on the tolerability (in combination with saidNK1-antagonist).

According to an embodiment, in the pharmaceutical composition Component(b), pramipexole or pharmaceutically acceptable salt or solvate thereof,is in an amount per unit form equivalent to from 0.125 mg to 21 mg, inparticular from 0.125 mg to less than 1.6 mg, from 1.6 mg to 21 mg, frommore than 4.5 mg to 21 mg or from more than 6 mg to 21 mg of pramipexoledihydrochloride monohydrate.

In particular, according to this embodiment the dose of pramipexole orpharmaceutically acceptable salt or solvate thereof per IR-unit form,for the treatment of a depressive disorder, including MDD, will rangefrom an amount equivalent to from 1.6 mg to 10.5 mg, from 1.8 to 10.5mg, from 2.4 mg to 10.5 mg or from 3 mg to 10.5 mg of pramipexoledihydrochloride monohydrate, depending on safety and tolerability (incombination with the NK1-antagonist).

The dose per unit form of pramipexole or pharmaceutically acceptablesalt or solvate thereof in an ER formulation, including slow-releasecompositions and transdermal therapeutic systems such as transdermalpatches, for the treatment of a depressive disorder, including MDD,according to this embodiment, will range from an amount that isequivalent to from more than 4.5 mg to 21 mg, in particular from 4.8 mgto 21 mg, or from more than 6 mg to 21 mg of pramipexole dihydrochloridemonohydrate, depending on the tolerability (in combination with saidNK1-antagonist).

In the case of separate (concurrent or sequential) administration ofsaid NK1-antagonist, in an effective amount per unit form, and of saidpramipexole, in an effective amount per unit form, each of them can bepackaged in a kit comprising said NK1-antagonist, in admixture with apharmaceutical carrier or vehicle, in a container; and said pramipexole,in admixture with a pharmaceutical carrier or vehicle, in another,separate container.

For the intended use in the treatment of a depressive disorder,including MDD, in combination with pramipexole, the NK1-antagonist isformulated in a pharmaceutical composition, wherein said NK1-antagonistis in admixture with a pharmaceutical carrier or vehicle.

For their concurrent administration for the treatment of depressivedisorder, including MDD, said NK1-antagonist and said pramipexole mayalso be formulated together and with a pharmaceutical carrier orvehicle, in a pharmaceutical composition (fixed-dose combination).

Fourth Aspect of the Invention

A fourth aspect of the present invention provides

-   -   the use of a NK1-antagonist for the manufacture of a medicament        for the treatment of a depressive disorder, including MDD, as a        fixed-dose combination consisting of or comprising a        pharmaceutical composition in dosage unit form which comprises,        as an active ingredient, said NK1-antagonist, in an effective        amount per unit form, and, as another active ingredient,        pramipexole or a pharmaceutically acceptable salt thereof, in an        effective amount per unit form, in admixture with a        pharmaceutical carrier or vehicle;    -   the use of a NK1-antagonist for the manufacture of a medicament        for the treatment of a depressive disorder, including MDD, as a        fixed-dose combination consisting or consisting essentially of a        pharmaceutical composition in dosage unit form which comprises,        as an active ingredient, said NK1-antagonist, in an effective        amount per unit form, in admixture with a pharmaceutical carrier        or vehicle; and, a pharmaceutical composition in dosage unit        form which comprises, as an active ingredient, pramipexole or a        pharmaceutically acceptable salt thereof, in an effective amount        per unit form, in admixture with a pharmaceutical carrier or        vehicle;    -   said medicament as a fixed dose combination for use in the        treatment of a depressive disorder, including MDD; and    -   a method for treating a depressive disorder, including MDD, in a        patient in need of said treatment which comprises administering        to said patient said medicament as a fixed-dose combination.

For this method (or use), the invention provides a medicament as afixed-dose combination consisting of or comprising a pharmaceuticalcomposition in dosage unit form which comprises

-   (a) a NK1-antagonist, in an amount per unit form of from 1 μg to 600    mg; and-   (b) pramipexole or a pharmaceutically acceptable salt thereof, in an    amount equivalent to from 0.125 mg to 45 mg of pramipexole    dihydrochloride monohydrate,    in admixture with a pharmaceutical carrier or vehicle, for use in    the treatment of a depressive disorder, including MDD, in a patient    in need of said treatment.

According to this embodiment of the fourth aspect of the invention, anyof the NK1-antagonists described in “The NK1-antagonist Component (a)”section may be used as Component (a) of said pharmaceutical composition,in an amount per unit form as described in said section, in a fixed dosecombination with pramipexole Component (b) in an amount per unit form asdescribed above in “The pramipexole Component (b)” section, in admixturewith a pharmaceutical carrier or vehicle.

For this method (or use), the invention provides a medicament as afixed-dose combination consisting of or comprising

-   (a) a pharmaceutical composition in dosage unit form which comprises    a NK1-antagonist, in an amount per unit form of from 1 μg to 600 mg,    in admixture with a pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition in dosage unit form which comprises    pramipexole or a pharmaceutically acceptable salt thereof, in an    amount equivalent to from 0.125 mg to 45 mg of pramipexole    dihydrochloride monohydrate, in admixture with a pharmaceutical    carrier or vehicle;

for use in the treatment of a depressive disorder, including MDD, in apatient in need of said treatment.

According to this embodiment, any of the NK1-antagonists described in“The NK1-antagonist Component (a)” section may be used in pharmaceuticalcomposition (a), in an amount per unit form as described in saidsection, and pramipexole as described above in “The pramipexoleComponent (b)” section may be used in pharmaceutical composition (b) inan amount per unit form as described therein.

According to an embodiment, said NK1-antagonist Component (a) or NK-1antagonist in pharmaceutical composition (a) is selected from the groupconsisting of aprepitant and pharmaceutically acceptable salts andsolvates thereof, in an amount per unit form equivalent to from 10 mg to250 mg of aprepitant; fosaprepitant and pharmaceutically acceptablesalts and solvates thereof, in an amount per unit form equivalent tofrom 10 mg to 250 mg of aprepitant; rolapitant and pharmaceuticallyacceptable salts and solvates thereof, in an amount per unit formequivalent to from 15 mg to 270 mg of rolapitant; and netupitant andpharmaceutically acceptable salts and solvates thereof, in an amount,per unit form, equivalent to from 300 mg to 600 mg; and said pramipexoleComponent (b) or pramipexole in pharmaceutical composition (b) is in anamount per unit form equivalent to a range selected from the groupconsisting of from 0.125 mg to 45 mg, from more than 4.5 mg to 45 mg,from more than 6 mg to 45 mg, from 10 mg to 45 mg, from 13 mg to 45 mg,and from 15 mg to 45 mg of pramipexole dihydrochloride monohydrate.

In pharmaceutical compositions described herein, the NK1-antagonistnormally is in an IR-unit form and said pramipexole may be in an IR-unitform or, preferably, in an ER-unit form. Said unit forms are describedin “The formulations” section below.

According to an embodiment, said fixed-dose combination comprises orconsists of a pharmaceutical composition comprising

-   (a) said NK1-antagonist, in an amount/unit form of from 1 μg to 600    mg; and-   (b) pramipexole or a pharmaceutically acceptable salt or solvate    thereof, in an amount per unit form equivalent to from 0.125 mg to    21 mg,    in admixture with a pharmaceutical carrier or vehicle, and is for    use for the treatment of depressive disorder, including MDD, in a    patient.

According to an embodiment, said fixed-dose combination comprises orconsists of

-   (a) a pharmaceutical composition comprising said NK1-antagonist, in    an amount/unit form of from 1 μg to 600 mg, in admixture with a    pharmaceutical carrier or vehicle; and-   (b) a pharmaceutical composition comprising pramipexole or a    pharmaceutically acceptable salt or solvate thereof, in an amount    per unit form equivalent to from 0.125 mg to 21 mg, in admixture    with a pharmaceutical carrier or vehicle;    for use for the treatment of depressive disorder, including MDD, in    a patient.

According to this embodiment, for said uses and method, in thefixed-dose combination said NK1-antagonist, in an amount of from 1 μg to600 mg, normally form 1 mg to 600 mg, and said pramipexole orpharmaceutically acceptable salt or solvate thereof, in an amount perunit form equivalent to from 0.125 mg to 21 mg, in particular from 0.125mg to less than 1.6 mg, from 1.6 mg to 21 mg, from more than 4.5 mg to21 mg or from more than 6 mg to 21 mg of pramipexole dihydrochloridemonohydrate, are mixed together and formulated in a pharmaceuticalcomposition, in admixture with a pharmaceutical carrier or vehicle, tobe administered to the patient suffering from a depressive disorder,including MDD.

The Formulations

NK1-antagonist may be formulated in a pharmaceutical composition,wherein said NK1-antagonist is in admixture with a pharmaceuticalcarrier or vehicle. Ppramipexole may also be formulated in apharmaceutical composition, wherein said pramipexole is in admixturewith a pharmaceutical carrier or vehicle.

In the above combinations, including fixed-dose combinations, of thepresent invention, the dose of pramipexole or pharmaceuticallyacceptable salt or solvate thereof, in pramipexole dihydrochloridemonohydrate, per unit form, is from 0.125 mg to 45 mg, in an IR- orER-formulation. Normally, i.e. in most patients suffering from adepressive disorder, including MDD, to be treated with said combination,said dose will range from 0.125 mg to 21 mg, in particular from 0.125 mgto less than 1.6 mg, advantageously from 1.6 mg 21 mg, from 1.8 mg to 21mg, from 2.4 mg to 21 mg, to 3 mg to 21 mg, more advantageously frommore than 4.5 mg to 21 mg, preferably from more than 6 mg to 21 mg from10 mg to 21 mg, from 13 mg to 21 mg or from 15 mg to 21 mg.

It is hereby specified that pramipexole, or pharmaceutically acceptablesalt or solvate thereof, at a dose per IR-unit form equivalent to from0.125 mg to less than 1.6 mg, in particular from 0.125 mg to 1.5 mg ofpramipexole dihydrochloride monohydrate dose per unit form, may possiblybe used as titration doses at the beginning of the treatment of an adultpatient or a pediatric patient, and that a dose per IR-unit form that isat least higher (1.08 times to 7 times higher) than the 1.5 mg maximumapproved dose per IR unit form is needed to treat depression in adultpatients. Thus, in order to be able to administer pramipexole at a dailydose of from more than 4.5 mg/day to 21 mg/day, advantageously from 5mg/day to 21 mg/day, preferably from more than 6 mg/day to 21 mg day orfrom 15 mg to 21 mg, in combination with a NK1-antagonist, newIR-formulations are needed for treating a patient suffering from adepressive disorder, including MDD.

In particular, the dose of pramipexole or pharmaceutically acceptablesalt or solvate thereof per IR-unit form, for the treatment of adepressive disorder, including MDD, will range from an amount equivalentto from 1.6 mg to 10.5 mg, from 1.8 to 10.5 mg, from 2.4 mg to 10.5 mg,from more than 3 mg to 10.5 mg, up to from 7.5 mg to 10.5 mg ofpramipexole dihydrochloride monohydrate, depending on safety andtolerability (in combination with the NK1-antagonist).

The dose of pramipexole or pharmaceutically acceptable salt or solvatethereof per ER-unit form, for the treatment of a depressive disorder,including MDD, will range from an amount equivalent to from more than4.5 mg to 21 mg, advantageously from more than 6 mg to 21 mg, up to from15 mg to 21 mg of pramipexole dihydrochloride monohydrate, depending onsafety and tolerability (in combination with the NK1-antagonist).

If the NK1-antagonist is aprepitant, the dose/unit form will range from10 mg to 250 mg.

If the NK1-antagonist is rolapitant, the dose/unit form, in combinationwith pramipexole or pharmaceutically acceptable salt thereof at theabove doses/unit form, will range from 30 mg to 270 mg.

The patients who tolerate pramipexole doses per unit form from more than21 mg to 45 mg, or even higher, will have largely overcome the titrationphase and will be regularly followed by their physician.

For their administration for the treatment of depressive disorder,including MDD, the NK1-antagonist and pramipexole or a pharmaceuticallyacceptable salt or solvate thereof are each formulated in apharmaceutical composition in admixture with a pharmaceutical carrier orvehicle.

In the pharmaceutical compositions of the present invention for oral,subcutaneous, intravenous, transdermal or topical administration, theactive ingredients are preferably administered in the form of dosageunits, in admixture with the classic pharmaceutical carriers orvehicles, as set forth above.

The pharmaceutical compositions thus obtained are concurrently orsequentially administered to a patient suffering from a depressivedisorder, including MDD.

Said NK1-antagonist and said pramipexole or a pharmaceuticallyacceptable salt or solvate thereof may also be formulated together in afixed-dose combination consisting of a pharmaceutical compositioncomprising said pramipexole or a pharmaceutically acceptable salt orsolvate thereof, and said NK1-antagonist, in admixture with apharmaceutical carrier or vehicle.

The dosage, i.e. the amount of active ingredient in a single dose(amount per unit form) to be administered to the patient, can varywidely depending on the age, weight, and the health condition of thepatient.

This dosage includes the administration of a NK1-antagonist dose from 1μg to 600 mg, normally from 1 mg to 600 mg or from 1 mg to 300 mg,according to the potency of said NK1-antagonist and the age of thepatient

In general, the dose of pramipexole or pharmaceutically acceptable saltor solvate thereof is in an amount per IR-unit form, in pramipexoledihydrochloride monohydrate, of from 0.125 mg to 22.5 mg, from more than1.5 mg to 22.5 mg, from 3 mg to 22.5 mg, from 5 mg to 22.5 mg, from 6.5mg to 22.5 mg or from 7.5 mg to 22.5 mg, depending on safety andtolerability (in combination with the NK1-antagonist) and includingdoses per IR-unit form to be used in the titration period.

In general, the dose of pramipexole or pharmaceutically acceptable saltor solvate thereof, per ER-unit form, is an amount-range, in pramipexoledihydrochloride monohydrate, of from 0.125 mg to 45 mg, from more than4.5 mg to 45 mg, from more than 6 mg to 45 mg, from 10 mg to 45 mg, from13 mg to 45 mg or from 15 mg to 45 mg, depending on safety andtolerability (in combination with the NK1-antagonist).

Normally, the dose of pramipexole or pharmaceutically acceptable salt orsolvate thereof per IR-unit form will be in an amount-range, inpramipexole dihydrochloride monohydrate, of from 0.125 mg to 10.5 mg,from 1.6 mg to 10.5 mg, from 3 mg to 10.5 mg, from 5 mg to 10.5 mg, from6.5 mg to 10.5 mg or from 7.5 mg to 10.5 mg depending on safety andtolerability (in combination with the NK1-antagonist).

The dose per unit form of pramipexole or pharmaceutically acceptablesalt or solvate thereof in an ER formulation, including slow-releasecompositions and transdermal therapeutic systems such as transdermalpatches, will normally in a range that is equivalent to from 0.375 mg to21 mg, from more than 4.5 mg to 21 mg, from more than 6 mg to 21 mg,from 10 mg to 21 mg, from 13 mg to 21 mg or from 15 g to 21 mg ofpramipexole dihydrochloride monohydrate, depending on the tolerability(in combination with said NK1-antagonist).

As set forth above, the pramipexole doses/unit forms include low dosesthat can be used especially in the case of the titration of thepramipexole daily dose or in the less frequent case of use in thetreatment of pediatric depressed patients.

The pharmaceutical compositions of the present invention are in unitform formulated with the classic excipients suitable for different waysof administration, as described above. Said unit forms are manufacturedaccording to conventional technologies allowing, for example, theformulation of the NK1-antagonist in an IR-form and of pramipexoledihydrochloride monohydrate in ER-form in the same unit-form.Particularly advantageous are the formulations in the form of tablets,multi-score tablets, multi-layer tablets, coated tables, orallydisintegrating tablets, extended release tablets, hard or soft capsules,multi-compartment capsules, extended-release capsules, patches fortransdermal administration, liquid oral solutions, syrups or suspensionsin a predetermined unit form, and vials for the intravenous orsubcutaneous administration.

The pharmaceutical compositions may be formulated in oral unit formssuch as tablets or gelatin capsules wherein pramipexole or apharmaceutically acceptable salt or solvate thereof or theNK1-antagonist or both the active ingredients are in admixture with acarrier or vehicle that may include a diluent, such as cellulose,dextrose, lactose, mannitol, sorbitol or sucrose; a lubricant, such as,acid, calcium or magnesium stearate, polyethylene glycol, silica, ortalc; and if needed, a binder such as magnesium aluminum silicate,gelatin, methylcellulose, sodium carboxymethylcellulose, orpolyvinylpyrrolidone.

Said oral forms may be tablets coated with sucrose or with variouspolymers; or, alternatively, the tablets can be manufactured by usingcarriers such as acrylic and methacrylic acid polymers and copolymers;cellulose derivatives such as hydroxypropylethylcellulose; or otherappropriate materials, to have a prolonged or delayed activity byprogressively releasing a predetermined quantity of pramipexole (orpharmaceutically acceptable salt or solvate thereof), or ofNK1-antagonist, or of both the active ingredients. The oral formulationscan also be in form of capsules allowing the extended release thepramipexole (or pharmaceutically acceptable salt or solvate thereof), orof NK1-antagonist, or of both the active ingredients.

As mentioned above, said oral unit forms may also be tablets or capsuleswherein one of the active ingredient is in an IR-formulation and theother one is in an ER-formulation. For example said unit form comprisesaprepitant or rolapitant in an IR-formulation and pramipexoledihydrochloride monohydrate in an ER-formulation, each at the amount perunit form as described above.

The pharmaceutical compositions may also be formulated in TTS, such as apatch formulation wherein the active ingredient or the mixture of theactive ingredients may comprise adjuvants such as D-sorbitol, gelatin,kaolin, methyl paraben, polysorbate 80, propylene glycol, propylparaben, povidone, sodium carboxymethylcellulose, sodium polyacrylate,tartaric acid, titanium dioxide, and purified water. A patch formulationmay also contain skin permeability enhancer such as lactate esters(e.g., lauryl lactate), triacetin or diethylene glycol monoethyl ether.

Accordingly, for example, pramipexole, preferably as a free base, may beformulated in a TTS, transdermally delivering a pramipexole effectivedose, as described in “The pramipexole Component (b)” section, normallythroughout the day; and, preferably, with a NK1-antagonist as describedbelow, r,

-   -   aprepitant be may formulated in an oral IR-form,    -   fosaprepitant meglumine may be formulated in a vial for        injection, and    -   rolapitant may be formulated in an oral IR-unit form,        each at a dose per unit form as described in “The NK1-antagonist        Component (a)” section.

In the case of pediatric or obese patients, the NK1-antagonist dailydose may be decided on the basis of the body weight. Thus, for example,aprepitant may be administered at a daily dose of from 0.67 to 2 mg/kg.

EXAMPLES Example 1

A Phase I study was conducted in subjects receiving a single oral doseof pramipexole dihydrochloride monohydrate (“pramipexole”) with orwithout a single oral dose of aprepitant. The study was a single center,single-blind study.

The objective of the study was to demonstrate that aprepitant couldsafely attenuate the gastro-intestinal side effects of pramipexole givenin doses equivalent or higher than those approved in the treatment ofParkinson's Disease or shown in clinical trials to be effective in thetreatment of depression.

To be enrolled in the study, participants the followinginclusion/exclusion key criteria:

Key Inclusion Criteria

-   1. Male and female subjects aged 20-45 years old both ages included.-   2. Females of childbearing potential must agree to be abstinent or    else use any two of the following medically acceptable forms of    contraception from the Screening Period through 14 days after the    study Exit Visit: condom with spermicidal jelly, diaphragm or    cervical cap with spermicidal jelly, or intrauterine device (IUD). A    female whose male partner has had a vasectomy must agree to use one    additional form of medically acceptable contraception. Subjects must    agree to practice the above birth control methods for 14 days after    the final visit as a safety precaution.-   3. Females of non-childbearing potential, defined as surgically    sterile (status post-hysterectomy, bilateral oophorectomy, or    bilateral tubal ligation) or post-menopausal for at least 12 months,    do not require contraception during the study. The reason must be    documented in the source documents.-   4. Males with female partners of childbearing potential must agree    to use a highly effective, medically acceptable form of    contraception from the Screening Period through 14 days after the    study Exit Visit. Males with female partners of childbearing    potential who themselves are surgically sterile (status post    vasectomy) must agree to use condoms with spermicide over the same    period of time. Male subjects must agree to practice the above birth    control methods for 14 days after the final visit as a safety    precaution.-   5. Subjects must be in good health as determined by their medical    history including personal and family psychiatric history and    results of physical examination, electrocardiogram (ECG), vital    signs, and laboratory tests. A subject with a medical abnormality    may be included only if the investigator or designee considers that    the abnormality will not introduce significant additional risk to    the subject's health or interfere with study objectives.-   6. Subjects must be able to clearly and reliably communicate changes    in their medical condition.-   7. Subjects with a body mass index (BMI) between 19.0 and 32.0 kg/m²    (both inclusive).-   8. Subjects able to swallow multiple pills or capsules    simultaneously.-   9. Subjects must have signed an informed consent form indicating    that they understand the purpose of and procedures required for the    study and are willing to participate in the study and comply with    the study procedures and restrictions.

Key Exclusion Criteria:

The criteria for exclusion of a subject from enrollment in the studywere as follows:

-   1. Any clinically relevant acute or chronic diseases which could    interfere with the subjects' safety during the trial, expose them to    undue risk, or interfere with the study objectives.-   2. History or presence of gastrointestinal, hepatic, or renal    disease or other condition known to interfere with the absorption,    distribution, metabolism or excretion of the study drugs.-   3. History of substance abuse, known drug addiction, or positive    test for drugs of abuse or alcohol.-   4. History of drug or other significant allergy.-   5. Known hypersensitivity to pramipexole, or to ondansetron or    similar serotonin receptor antagonists, or to aprepitant or similar    Substance P/NK1 receptor antagonists.-   5. History of and/or current QT interval prolongation, congenital    long QT syndrome, electrolyte abnormalities (e.g., hypokalemia or    hypomagnesemia), congestive heart failure, bradyarrhythmias or other    medicinal products that lead to QT prolongation or 1st degree AV    block at Screening, Day −1, or pre-dose, ≥450 QTcF for males and    ≥470 QTcF for females.-   7. Treatment with centrally active drugs or antiemetics, within 1    months of study entry.-   8. Tobacco or nicotine users (except subjects who stopped using    tobacco or nicotine 1 year or more before enrollment in the study).-   9. Excessive daily consumption of xanthines containing drinks    (i.e. >500 mg/day of caffeine).-   10. Subjects unwilling to curtail prolonged intensive physical    exercise during the study conduct (from the Screening visit until    the last dose of study drug).-   11. Positive test result for hepatitis B surface antigen, hepatitis    C antibody.-   12. Positive test result for HIV 1 or 2 serology.-   13. Likely to need any medical or dental treatment during the study    period.-   14. Use of any prescription or over-the-counter medication within 14    days prior to admission on Day −1. In addition any medications with    central effects are prohibited for a period equal to 5 times the    drug half-life prior to admission (Day −1), should this period be    longer than 14 days.-   15. Subjects unlikely to co-operate during the study, and/or be    questionably compliant in the opinion of the investigator.-   16. Subjects unable to be contacted in case of an emergency.-   17. Intake of an investigational drug within 30 days of study entry.-   18. Show evidence of suicidal ideation within the last 6 months as    assessed by the C-SSRS (Columbia Suicide Severity Rating Scale) at    Screening.

Following enrollment in the study, participants received singleincreasing oral doses of pramipexole given once daily in the morning(Period 1 of the study). The starting dose of pramipexole was 0.5 mg andthe dose was increased daily by 0.5 mg increments. Once a subject hadreached his/her first intolerable dose (FID-1), upward dose escalationwas discontinued. First intolerable dose (FID) was defined as:

-   -   One (1) episode of vomiting; or    -   Two (2) episodes of retching, or    -   One (1) episode of severe nausea (Grade 3; defined as nausea        interfering with activities of daily living or inadequate oral        caloric or fluid intake; tube feeding, total parenteral        nutrition or hospitalization indicated) lasting more than 1        hour, or    -   Three (3) consecutive episodes at every 4 hour ratings of        moderate nausea (Grade 2; defined as subjectively symptomatic,        but not interfering with activities of daily living), or    -   One (1) episode of moderate diarrhea (Grade 2; defined as 4-6        stools more than at baseline).

When a subject reached FID-1 on pramipexole alone, the subject waswashed out for at least 5 days, and then entered Period 2 of the studyduring which the subject received single daily oral doses of pramipexolestarting at 0.5 mg and titrated upward by 0.5 mg increments, togetherwith oral aprepitant (80 mg) until subjects again reached an intolerabledose defined as above. The FID on oral pramipexole plus oral aprepitantwas referred to as FID-2.

If a subject reached FID-2 during Period 2 at the same or lower dosethan FID-1, and providing the investigator judged there were no safetyissues and the subject was consenting, the subject received the samedose of pramipexole as the FID-2 dose together with a higher dose oforal aprepitant (120 mg) on the next day and the protocol specified thatsaid subject should continue with the remainder of the dose titrationwith the higher dose of oral aprepitant (120 mg) until they reach theintolerable dose (FID2+). All other provisions of the protocol remainedunchanged. Assessments were the same as those planned for the doseescalation day.

On each study day, subjects were followed up for up to 8 hours followingdrug administration for AEs, vital signs, ECGs. In addition, alaboratory panel was taken at screening and at the end of the study.

Four subjects were enrolled in the study. The following Table 1summarizes the demographic characteristics of the subjects.

TABLE 1 Demographic Characteristics of Subjects Enrolled in the StudySubject ID Gender Age (years) Baseline Weight (kg) 1001 (019) Female 4076.4 kg 1006 (001) Male 41 99.1 kg 1007 (004) Male 38 64.9 kg 1008 (008)Male 39 81.8 kg

All subjects reached FID-1 (pramipexole alone) during the study. Thedose limiting toxicity was gastro-intestinal adverse events in all 4subjects. During Period 2 of the study, all 4 subjects tolerated themaximum pramipexole dose allowed by the protocol of 6 mg and thereforenone of them reached FID-2 (pramipexole with aprepitant). In otherwords, concomitant administration of aprepitant with pramipexoleprevented the occurrence of dose-limiting gastro-intestinal adverseevents associated with high doses of pramipexole. Table 2 lists for eachsubject the values for FID-1 (on pramipexole alone) and FID-2 (onpramipexole+aprepitant).

TABLE 2 Listing of First Intolerable Doses (FID) values FID-2 FID-1FID-1 Dose Limiting Pramipexole + Subject ID (Pramipexole alone) AdverseEvent Aprepitant 1001 2.5 mg GI issues >6.0 mg 1006 0.5 mg Moderatenausea >6.0 mg 1007 4.5 mg Severe nausea >6.0 mg 1008 1.5 mgVomiting >6.0 mg

As shown in the following Table 3, the Maximum Tolerated Dose (MTD)during Period 2 was higher than MTD during Period 1 in all subjects, andin 3 subjects MTD-2 was increased by more than 3-fold.

TABLE 3 Listing of Maximum Tolerated Doses (MTD) Maximal Tolerated DoseMTD-1 Pramipexole + Subject ID (Pramipexole alone) Aprepitant MTD2/MTD11001 2.0 mg ≥6.0 mg ≥3.0 1006 NA (not tolerated at ≥6.0 mg ≥12.0 0.5 mg)1007 4.0 mg ≥6.0 mg ≥1.5 1008 1.0 mg ≥6.0 mg ≥6.0 MTD: Maximum ToleratedDose

Taken together, results showed that the co-administration of aprepitantwith pramipexole attenuated dose-limiting gastro-intestinal adverseeffects reported with pramipexole alone, thus showing that aNK1-antagonist enables the administration to a human being ofpramipexole in doses otherwise non-tolerated when administeringpramipexole alone.

In conclusion, the co-administration of aprepitant with pramipexoleinhibited the occurrence of gastro-intestinal AEs associated withpramipexole given alone, thus enabling doses of pramipexole to be safelyand tolerably raised by more than 2-fold, thereby allowing a far greaterefficacy of this drug. In particular, these results show that theprotective action of a NK1-antagonist allows the safe treatment of ahuman with pramipexole not only within the pramipexole approved doserange but also at doses that are higher than its maximum recommendeddose, as well as at doses that are higher than a maximal tolerated doseof pramipexole when administered alone.

REFERENCES

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1-18. (canceled)
 19. A pharmaceutical combination comprising, asComponent (a) a NK1-antagonist, in a pharmaceutical composition indosage unit form comprising, as an active ingredient, saidNK1-antagonist, in an amount per unit form of from 1 mg to 600 mg, inadmixture with a pharmaceutical carrier or vehicle, and (b) pramipexoleor a pharmaceutically acceptable salt or solvate thereof, in an amountper unit form equivalent to from 0.125 mg to 21 mg of pramipexoledihydrochloride monohydrate, in admixture with a pharmaceutical carrier.20. The combination of claim 19, wherein said pramipexole orpharmaceutically acceptable salt or solvate thereof is in an amount perunit form equivalent to from more than 4.5 mg to 21 mg or from more than6 mg to 21 mg of pramipexole dihydrochloride monohydrate.
 21. Thecombination of claim 19, which is a fixed-dose combination consisting ofa pharmaceutical composition comprising (a) said NK1-antagonist, in anamount per unit form of from 1 mg to 600 mg; and (b) pramipexole or apharmaceutically acceptable salt or solvate thereof, in an amount perunit form equivalent to from 0.125 mg to 21 mg of pramipexoledihydrochloride monohydrate, in admixture with a pharmaceutical carrieror vehicle.
 22. The combination of claim 21, wherein, in saidpharmaceutical composition, said pramipexole or pharmaceuticallyacceptable salt or solvate thereof is in an amount per unit formequivalent to from more than 4.5 mg to 21 mg or from more than 6 mg to21 mg of pramipexole dihydrochloride monohydrate.
 23. The combination ofclaim 19, wherein said NK1-antagonist is aprepitant, in an amount perunit form in a range of from 10 mg to 250 mg.
 24. The combination ofclaim 21, wherein said NK1-antagonist is aprepitant, in an amount perunit form in a range of from 10 mg to 250 mg.